CN1395566A - Corticotropin releasing factor antagonists - Google Patents

Corticotropin releasing factor antagonists Download PDF

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Publication number
CN1395566A
CN1395566A CN01803846A CN01803846A CN1395566A CN 1395566 A CN1395566 A CN 1395566A CN 01803846 A CN01803846 A CN 01803846A CN 01803846 A CN01803846 A CN 01803846A CN 1395566 A CN1395566 A CN 1395566A
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Prior art keywords
alkyl
group
methyl
cycloalkyl
dimethyl
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CN01803846A
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Chinese (zh)
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陈玉凭梁
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Pfizer Products Inc
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Pfizer Products Inc
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Abstract

The present invention relates to corticotropin-releasing factor (CRF) antagonists having the formulae (I), (II) or (III), wherein the dashed lines, A, B, Y, Z, G, R<3>, R<4>, R<5>, R<6>, R<16> and R<17> are as defined in the application, and processes for preparing them. These compounds and their pharmaceutically acceptable salts are useful in the treatment disorders including CNS and stress-related disorders.

Description

Corticotropin releasing factor antagonists
Background of invention
The present invention relates to pyridine, pyrimidine, hypoxanthine, Pyrrolopyrimidine thion and pyrrolopyridinone, their preparation method contains their pharmaceutical composition and uses them to treat the method for some central nervous system (CNS) and other obstacle.
The CRF antagonist on August 12nd, 1986 disclosed U.S. patent mention in 4,605,642 and 1991 on November 5, disclosed 5,063,245, be called peptide and pyrazolone.The CRF antagonist also is described in the disclosed U.S. patent 5,96,479 on October 5th, 1999.The importance of CRF antagonist is delivered in the literature, as, being described in the U.S. patent 5,063,245, the document is hereby incorporated by.The CRF antagonist has the up-to-date summary of different activities to be found people such as M.J.Owens, the Pharm.Rev.43 volume, and 425-473 page or leaf (1991), the document also is hereby incorporated by.Based on the research in these two and other reference, the CRF antagonist is effectively for wide region and treatment stress diseases related, as stress the inductive infection in depression, anxiety, headache, irritable bowel syndrome, diseases associated with inflammation, immunosuppression, alzheimer's disease, gastrointestinal disease, anorexia nervosa, hemorrhagic stress reaction, medicine and alcohol withdrawal symptom, drug habit, Infertility, head trauma, apoplexy and human body and the animal body.The purposes that the CRF antagonist is used for the treatment of syndrome X also is described in the U.S. patent application No.09/696 that submitted on October 26th, 2000, among the european patent application No.00309441.4 that on October 26th, 822 and 2000 submitted to, these documents are incorporated herein by reference in full at this.Use the method for CRF antagonist for treating congestive heart failure to be described in the U.S. series No.09/248 that submitted on February 10th, 1999, in 073, be U.S. patent 6,043 now, in 260 (on March 28th, 2000 is open), these documents also are incorporated herein by reference in full at this.
Summary of the invention
The invention provides compound and its pharmaceutical salts with following general formula, Or Wherein dotted line is represented two keys of choosing wantonly, and condition is to work as C ---When the dotted line among the G is represented two key, N (R) then ---Dotted line among the C is not represented two keys; With condition is to work as N (R) ---When the dotted line among the C was represented two key, R did not exist and C in general formula III ---Dotted line among the G is not represented two keys;
A is-CR or N;
B is-NR R ,-CR R R ,-C (=CR R) R ,-NHCHR R ,-OCHR 1R 2,-CHR 1R 2,-CHR 2OR 1,-CHR 1OR 2,-CHR 2R 1,-C () R 2,-C (O) R 2,-CHR 2NR 1R 2,-CHR 1NHR 2,-CHR 1N (CH 3) R 2, or-NR 12NR 1R 2
Work as C ---When the dotted line among the G was represented two key, then G was hydrogen, oxygen, sulphur, NH or N (C 1-C 4Alkyl);
Work as C ---When the dotted line among the G was not represented two key, then C---G was C (H) (NH 2), CH 2, C (H) (methoxyl group), C (H) (oxyethyl group), C (H) (O (C 3-C 4Alkyl)), C (H) (halogen), C (H) (trifluoromethoxy), C (H) (methyl), C (H) (ethyl), C (H) (C 3-C 4Alkyl), C (H) (S (C 1-C 4Alkyl)) C (C, 1-C 4Alkyl) (C 1-C 4Alkyl), cyclopropyl, C (H) (cyclopropyl), sulfo-methoxyl group, C (H) (H 2), C (H) (HCH 3), C (H) ((CH 3) 2) or C (H) (trifluoromethyl);
C wherein ---Cyclopropyl, methoxyl group, oxyethyl group, C 3-C 4Alkyl and C 1-C 4Alkyl can be randomly replaced by a H, methoxyl group or trifluoromethoxy, or can be randomly-individual fluorine atom replaces;
Be CH or;
Be H,, S ,-(C 1-C 2Alkyl) ,-C () C 3, or-C ( 13 14), wherein 13With 14Separately randomly, be hydrogen, trifluoromethyl or methyl, or 13With 14One be that cyano group and another are hydrogen or methyl, or-C ( 13 14) be cyclopropyl, or nitrogen or CH and formation and 5Five yuan of condensed or hexa-member heterocycle, this ring randomly comprise two or three be independently selected from oxygen, nitrogen, 12, and S () mIn addition assorted member, and randomly comprise-individual pair key and randomly by halogen, C 1-C 4Alkyl ,-(C 1-C 4Alkyl), H 2, HCH 3, (CH 3) 2, C 3, or C 3Replace, condition is that this ring does not comprise any-S-S-,-S--,--S-or---key and do not comprise more than two oxygen or S () mThe xenogenesis member;
1Be C () H, C () (C 1-C 6Alkyl), C () (C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl), C () (C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), C () (C 1-C 6Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-C () (C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl), C 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 4-C 8Heterocyclylalkyl, (C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-(C 1-C 6Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl) or--aryl or--(C 1-C 6Alkylidene group)-aryl; Wherein aryl, C 4-C 8Heterocyclylalkyl, C 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkylidene and C 1-C 6Alkylidene group can each randomly replaced independently by-individual fluorine and can each independently randomly by one or two substituting group 8Replace, 8Be independently selected from C 1-C 4Alkyl, C 3-C 8Cycloalkyl, hydroxyl, fluorine, chlorine, bromine, iodine, C 3,--(C 1-C 6Alkyl),--(C 3-C 5Cycloalkyl),--C-(C 1-C 4Alkyl),--C-H (C 1-C 4Alkyl),--C-( 24) ( 25) ,-( 24) ( 25) ,-S (C 1-C 4Alkyl) ,-S (C 3-C 5Cycloalkyl) ,-(C 1-C 4Alkyl) C (C 1-C 4Alkyl) ,-HC (C 1-C 4Alkyl) ,-C (C 1-C 4Alkyl) ,-CH (C 1-C 4Alkyl) ,-C (C 1-C 4Alkyl) (C 1-C 2Alkyl), CN, NO 2,-OSO 2C 1-C 4Alkyl), S +C 1-C 6Alkyl) C 1-C 2Alkyl) -,-SO C 1-C 4Alkyl) and-SO 2C 1-C 4Alkyl); And wherein 1C 1-C 6Alkyl, C 1-C 6Alkylidene group, C 5-C 8Cycloalkyl, C 5-C 8Cycloalkylidene and C 5-C 8The Heterocyclylalkyl part can randomly comprise-individual pair key or triple bond; Wherein 8C 1-C 4Moieties and C 1-C 6Moieties can be chosen wantonly independently by hydroxyl, C 1-C 4Alkyl, amino, aryl ,-C 2-aryl, C 3-C 5Cycloalkyl or-O-C 1-C 4Alkyl) replaces and can be randomly replaced by-individual fluorine and can randomly comprise-individual pair key or triple bond; Wherein 1Each heterocyclic radical comprise-individual oxygen, the SO of being selected from) m, nitrogen and N 12Hetero moiety;
2Be hydrogen, C 1-C 12Alkyl, C 3-C 8Cycloalkyl, C 4-C 6Heterocyclylalkyl ,-C 1-C 6Alkylidene group) C 3-C 8Cycloalkyl) ,-C 3-C 8Cycloalkylidene) C 3-C 8Cycloalkyl) ,-C 1-C 6Alkylidene group) C 4-C 8Heterocyclylalkyl) ,-C 3-C 8Cycloalkylidene) C 4-C 8Heterocyclylalkyl), aryl ,-C 1-C 6Alkylidene group) aryl or-C 3-C 8Cycloalkylidene) aryl); Wherein each is above-mentioned 2Group can be randomly by-individual chlorine, fluorine and the C of being selected from 1-C 6The substituting group of alkyl replaces, wherein-and one of individual substituting group can further be selected from bromine, iodine, C 1-C 6Alkoxyl group ,-O ,-O-CO-C 1-C 6Alkyl) ,-O-CO-NC 1-C 4Alkyl) C 1-C 2Alkyl) ,-SC 1-C 6Alkyl) ,-and S O) C 1-C 6Alkyl) ,-SO) 2C 1-C 6Alkyl), S +C 1-C 6Alkyl) C 1-C 2Alkyl) -, CN and NO 2, and wherein 2C 1-C 12Alkyl ,-C 1-C 6Alkylidene group) ,-C 5-C 8Cycloalkyl) ,-C 5-C 8Cycloalkylidene) and-C 5-C 8Heterocyclylalkyl) part can randomly comprise-individual pair key or triple bond; And wherein 2Each Heterocyclylalkyl comprise-individual oxygen, the SO of being selected from) m, nitrogen and N 12Hetero moiety;
Or work as 1With 2As at-NC 12,-OC 12,-SC 12,-C 12, or N 12When middle, 1With 2Can form unit-unit ring, this ring can randomly comprise one or two pair key and one of them or two ring carbon can be randomly by oxygen, SO) m, and N 12Replace; And this carbocyclic ring can be randomly by-individually be selected from following substituting group and replace: hydroxyl, C 1-C 4Alkyl, fluorine, chlorine, bromine, iodine, C 3,-O-C 1-C 4Alkyl) ,-O-CO-C 1-C 4Alkyl) ,-O-CO-NC 1-C 4Alkyl) ,-O-CO-NC 1-C 4Alkyl) C 1-C 2Alkyl) ,-NC 1-C 4Alkyl) ,-NC 1-C 2Alkyl) C 1-C 4Alkyl) ,-SC 1-C 4Alkyl) ,-NC 1-C 4Alkyl) COC 1-C 4Alkyl) ,-NCOC 1-C 4Alkyl) ,-COOC 1-C 4Alkyl) ,-CONC 1-C 4Alkyl) ,-CONC 1-C 4Alkyl) C 1-C 2Alkyl), CN, NO 2,-OSO 2C 1-C 4Alkyl) ,-SOC 1-C 4Alkyl) and-SO 2(C 1-C 4Alkyl), wherein one of this 1-3 substituting group can further be selected from phenyl;
R 3Be methyl, ethyl, fluorine, chlorine, bromine, iodine, cyano group, methoxyl group, OCF 3, NH 2,-NH (C 1-C 2Alkyl) ,-NHCOCF 3,-N (CH 3) 2,-NHCH 2CF 3, S (O) m(C 1-C 4Alkyl), CONH 2,-CONHCH 3,-CON (CH 3) 2,-CF 3, or CH 2OCH 3
R 4Be hydrogen, C 1-C 4Alkyl, C 3-C 5Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 5Cycloalkyl) ,-(C 3-C 5Cycloalkylidene) (C 3-C 5Cycloalkyl), cyano group, fluorine, chlorine, bromine, iodine ,-OR 24, C 1-C 6Alkoxyl group ,-O-(C 3-C 5Cycloalkyl) ,-O-(C 1-C 4Alkylidene group) (C 3-C 5Cycloalkyl) ,-O-(C 3-C 5Cycloalkylidene) (C 3-C 5Cycloalkyl), CH 2SC (S) O (C 1-C 4Alkyl), CH 2OCF 3,-CF 3, amino, nitro ,-NR 24R 25,-(C 1-C 4Alkylidene group) OR 24,-(C 1-C 4Alkylidene group) Cl ,-(C 1-C 4Alkylidene group) NR 24R 25,-NHCOR 24,-NHCONR 24R 25,-C=NOR 24, NHNR 24R 25, S (O) mR 24,-C (O) R 24,-OC (O) R 24,-C (O) CN ,-C (O) NR 24R 25,-C (O) NHNR 24R 25, and-COOR 24, R wherein 4Alkyl and alkylidene group can randomly comprise one or two pair key or triple bond and can be independently randomly independently by 1-2 substituent R 10Replace R 10Be independently selected from hydroxyl, amino ,-NHCOCH 3,-NHCOCH 2Cl ,-NH (C 1-C 2Alkyl) ,-N (C 1-C 2Alkyl) (C 1-C 2Alkyl) ,-COO (C 1-C 4Alkyl) ,-COOH ,-CO (C 1-C 4Alkyl), C 1-C 6Alkoxyl group, C 1-C 3Alkylthio, cyano group and nitro and contain the substituting group that 1-4 is independently selected from fluorine and chlorine;
R 5Be aryl or heteroaryl and by 1-4 substituent R 27Replace R 27Be independently selected from halogen, C 1-C 10Alkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 1-C 4Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkyl) ,-(C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl), C 1-C 4Haloalkyl, C 1-C 4Halogenated alkoxy, nitro, cyano group ,-NR 24R 25,-NR 24COR 25,-NR 24CO 2R 26,-COR 24,-OR 25,-CONR 24R 25,-CO (NOR 22) R 23,-CO 2R 26,-C=N (OR 22) R 23, and S (O) mR 23This C wherein 1-C 10Alkyl, C 3-C 8Cycloalkyl, (C 1-C 4Alkylidene group), (C 3-C 8Cycloalkyl), (C 3-C 8Cycloalkylidene) and (C 4-C 8Heterocyclylalkyl) group can randomly be independently selected from following substituting group replacement: C by 1-3 1-C 4Alkyl, C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), C 1-C 4Haloalkyl, hydroxyl, C 1-C 6Alkoxyl group, nitro, halogen, cyano group ,-NR 24R 25,-NR 24COR 25,-NR 24CO 2R 26,-COR 24,-OR 25,-CONR 24R 25,-CO 2R 26,-CO (NOR 22) R 25, and S (O) mR 23And R wherein 5That two adjacent substituting groups of group can form is saturated or unsaturated, be fused to R 5On 5-7 unit ring, this ring randomly comprises-individual, two, or three be independently selected from O, S (O) mWith the xenogenesis member of N, but without any-S-S-,-O-O-,-S-O-or-N-S-key and this ring can be randomly by C 1-C 4Alkyl, C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), C 1-C 4Haloalkyl, nitro, halogen, cyano group ,-NR 24R 25,-NR 24COR 25,-NR 24CO 2R 26,-COR 24,-OR 25,-CONR 24R 25,-CO 2R 26,-CO (NOR 26) R 25, and S (O) mR 23Replace; The optional substituent R of this 1-4 wherein 27One of can further be selected from-SO 2NH (C 1-C 4Alkyl) ,-SO 2NH (C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-SO 2NH (C 3-C 8Cycloalkyl) ,-SO 2NH (C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-SO 2N (C 1-C 4Alkyl) (C 1-C 2Alkyl) ,-SO 2NH 2,-NHSO 2(C 1-C 4Alkyl) ,-NHSO 2(C 3-C 8Cycloalkyl) ,-NHSO 2(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) and-NHSO 2(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl); And R wherein 5Alkyl and alkylidene group can randomly comprise two keys or triple bond independently;
R 6Be hydrogen, C 1-C 4Alkyl, C 3-C 8Cycloalkyl ,-(C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl) or-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), wherein this alkyl or cycloalkyl can randomly be replaced by a hydroxyl, methoxyl group, oxyethyl group or fluorin radical;
Or wherein compound is the compound of general formula I I, R 6And R 4(=O) group maybe can connect to form 3-8 unit carbocyclic ring, randomly comprises 1-3 two keys and randomly comprise one, two or three to be selected from oxygen, SO can to form oxo together m, N and NR 12The xenogenesis ring members, but do not comprise any-O-O-,-S-O-,-S-S-or-the N-S-key, and further randomly by C 1-C 4Alkyl or C 3-C 8Cycloalkyl substituted, wherein this C 1-C 4Alkyl substituent can randomly comprise two keys or triple bond;
R 7Be hydrogen, methyl, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl ,-O (C 1-C 2Alkyl) ,-O (cyclopropyl) ,-COO (C 1-C 2Alkyl) ,-COO (C 3-C 8Cycloalkyl) ,-OCF 3, CF 3,-CH 2OH or CH 2OCH 3
R 11Be hydrogen, hydroxyl, fluorine, oxyethyl group or methoxyl group;
R 12Be hydrogen or C 1-C 4Alkyl;
R 16And R 17Each is hydrogen, hydroxyl, methyl, ethyl, methoxyl group or oxyethyl group independently, except R 16And R 17Both are not methoxy or ethoxy simultaneously;
Or R 16And R 17Form oxo (=O) group together;
Or R 16And R 17Connection to be to form 3-8 unit carbocyclic ring, randomly comprises 1-3 two keys and randomly comprise to be selected from O, SO m, N and NR 12The xenogenesis ring members, but do not comprise any-O-O-,-S-O-,-S-S-or-N-S-key and further randomly by C 1-C 4Alkyl or C 3-C 6Cycloalkyl substituted, wherein this C 1-C 4Alkyl substituent can randomly comprise two keys or triple bond;
R 22Be independently selected from hydrogen, C in each case 1-C 4Alkyl, C 1-C 4Haloalkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl group, C 3-C 8Cycloalkyl ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) and-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl);
R 23Be independently selected from C in each case 1-C 4Alkyl, C 1-C 4Haloalkyl, C 2-C 8Alkoxyalkyl, C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), aryl ,-(C 1-C 4Alkylidene group) aryl, piperidines, tetramethyleneimine, piperazine, N methyl piperazine, morpholine and thiomorpholine;
R 24And R 25Be independently selected from hydrogen, C in each case 1-C 4Alkyl, C 1-C 4Haloalkyl, particularly CF 3, CHF 2, CF 2CF 3, or CH 2CF 3,-(C 1-C 4Alkylidene group) OH ,-(C 1-C 4Alkylidene group)-O-(C 1-C 4Alkyl) ,-(C 1-C 4Alkylidene group)-O-(C 3-C 5Cycloalkyl), C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-C 4-C 8Heterocyclylalkyl ,-(C 1-C 4Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl), aryl and-(C 1-C 4Alkylidene group) aryl, wherein-C 4-C 8Heterocyclylalkyl can each independently randomly by aryl, CH 2-aryl or C 1-C 4Alkyl replaces, and can randomly comprise one or two pair key or triple bond; Or work as R 24And R 25Be as NR 24R 25,-C (O) NR 24R 25,-(C 1-C 4Alkylidene group) NR 24R 25, or-NHCONR 24R 25, NR then 24R 25Can further randomly form 4-8 unit heterocycle, randomly comprise one or two and be independently selected from S (O) m, oxygen, nitrogen and NR 12In addition assorted member and randomly comprise 1-3 two keys;
R 26Be independently selected from C in each case 1-C 4Alkyl, C 1-C 4Haloalkyl, C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), aryl and-(C 1-C 4Alkylidene group) (aryl); With
Wherein each m is 0,1 or 2 independently,
Condition be the Heterocyclylalkyl of general formula I, II, III compound do not comprise any-S-S-,-S-O-,-N-S-or-O-O-key and not comprising more than two oxygen or S (O) mThe xenogenesis member.
In one embodiment, the invention provides the compound of general formula I or II, wherein R 4Be-NHCH 2CF 3,-CONHNH 2,-CONHNHCH 3In another embodiment, R 4Be-OCF 3Or fluorine.In another embodiment, R 4Be-OCHF 2
In another embodiment, the invention provides general formula I or II, the compound of preferred formula I, wherein R 4Be-C (O) NR 24R 25Or-C (O) NHNR 24R 25In preferred embodiments, R 4Be-C (O) NR 24R 25If R 4Be-C (O) NR 24R 25Or-C (O) NHNR 24R 25, R then 24And R 25Be independently selected from hydrogen and C In a more specific embodiment 1-C 4Alkyl.In another embodiment, R 4Be-C (O) NH 2Or-C (O) NHCH 3In another embodiment, R 4Be-C (O) N (CH 3) 2
In another more specific embodiment, the invention provides above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-C (O) NHCH 2(C 3-C 5Cycloalkyl) ,-C (O) NH (C 3-C 5Cycloalkyl) ,-C (O) N (C 3-C 5Cycloalkyl) 2,-C (O) NR 24R 25, R wherein 24And R 25Form 4,5, or 6 yuan of heterocycles ,-C (O) NH (C 4-C 8Heterocyclylalkyl) or-C (O) NH (CH 2(C 4-C 8Heterocyclylalkyl)).
In another embodiment, the invention provides general formula I or II, the compound of preferred I, wherein R 4Be-(C 1-C 4Alkylidene group) NR 24R 25If R 4Be-(C 1-C 4Alkylidene group) NR 24R 25, R then 24And R 25Be independently selected from hydrogen, C In a more specific embodiment 1-C 4Alkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) and C 3-C 8Cycloalkyl.
In another embodiment, the invention provides the compound of above-mentioned general formula I or II, wherein R 4Be-OCH 2(C 3-C 5Cycloalkyl) ,-O (C 3-C 5Cycloalkyl) ,-SCH 2(C 3-C 5Cycloalkyl) or-S (C 3-C 5Cycloalkyl).
In another embodiment of the invention, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-COOCH 3In another embodiment of the invention, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-COOCH 2CH 3
Another embodiment of the invention provides above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-OCH 3In another embodiment of the invention, provide the compound of general formula I or II, wherein R 4Be-CH 3In another embodiment, R 4Be-CH 2CH 3In another embodiment, R 4Be chlorine.In another embodiment, R 4It is bromine.
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-CF 3
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-CH 2OH.
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-CH 2OCH 3
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-CH 2OCF 3
In another embodiment, general formula I or II, the compound of preferred I as defined above, and R 4Be-SCH 3
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-S (O) CH 3
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-S (O) 2CH 3
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-C (O) CH 3
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-NR 24R 25Preferably, R 24And R 25Be C 1-C 4Alkyl or hydrogen.In a more specific embodiment, R4 is-NH 2,-NHCH 3, or-N (CH 3) 2
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-NO 2
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-CH (OH) CH 3
In another embodiment, provide above-mentioned general formula I or II, the compound of preferred I, wherein R 4Be-CN.
In another embodiment, the invention provides above-mentioned general formula I, II, or the compound of III, wherein B is-NR 1R 2Or-NHCHR 1R 2If B is-NR 1R 2, R 1C preferably 1-C 6Alkyl, C 3-C 8Cycloalkyl or (C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl), more preferably (C 1-C 6Alkylidene group) (C 3-C 8And R cycloalkyl), 2Preferably-C 1-C 12Alkyl randomly comprises two keys of 1-3 or triple bond and randomly by 1-3 fluorine atom replacement.Preferably, B is-N (CH 2-cyclopropyl) (CH 2CH 3) or-N (CH 2-cyclopropyl) (CH 2CF 3).
If B is-NHCHR 1R 2, R then 1Preferably-C (O) H ,-C (O) (C 1-C 6Alkyl) or-C 1-C 6Alkyl, wherein this C 1-C 6Alkyl randomly is independently selected from-C by 1-6 fluorine atom or one or two 1-C 4Alkyl, hydroxyl and-O (C 1-C 6Alkyl) R 8Replace, and R 2Preferably-C 1-C 12Alkyl randomly comprises 1-3 two keys or triple bond and randomly is selected from fluorine and C by 1-3 1-C 6The substituting group of alkyl replaces.Preferably, if B be-NHCHR 1R 2, R then 1Be independently selected from-CH 2CH 3With-CF 2CH 3, and R 1Be independently selected from-CH 2CH 3,-CF 2CH 3,-CH (OH) CH 3,-CH (OCH 3) CH 3,-CH (OH) (CH 3) 2, and-C (O) CH 3Preferred B is-NHCH (CH 2CH 3) 2,-NHCH (CH 2CH 3) (CF 2CH 3) ,-NHCH (CF 2CH 3) 2,-NHCH (CH (OH) CH 3) (CF 2CH 3) ,-NHCH (CH (OH) CH 3) (CH 2CH 3) ,-NHCH (CH (OCH 3) CH 3) (CH 2CH 3) ,-NHCH (C (O) CH 3) (CH 2CH 3) ,-NHCH (C (O) CH 3) (CF 2CH 3) ,-NHCH (C (OH) (CH 3) 2) (CH 2CH 3) or NHCH (C (OH) (CH 3) 2) (CF 2CH 3).
Or preferred, B is-N (CH 2-cyclopropyl) (CH 2CH 3) ,-NHCH (CH 2CH 3) 2,-NHCH (CH (OH) CH 3) (CF 2CH 3) ,-NHCH (CH (OH) CH 3) (CH 2CH 3) ,-NHCH (CH (OCH 3) CH 3) (CH 2CH 3) ,-NHCH (C (O) CH 3) (CH 2CH 3) or-NHCH (C (OH) (CH 3) 2) (CH 2CH 3).
In another embodiment of the invention, B is selected from-OCHR 1R 2, SCHR 1R 2,-CHR 1NHR 2,-CHR 1N (CH 3) R 2,-CHR 2OR 1, or-CHR 1OR 2
In another embodiment of the invention, provide the I of above-mentioned general formula definition, II, or the compound of III, wherein R 3Be methyl, ethyl, O-CH 3,-OCF 3, Cl, S-CH 3, or CF 3Preferred R 3It is methyl.
In another embodiment of the invention, provide the compound of above-mentioned general formula III, wherein C ---N (R 6) in dotted line represent two keys, and C ---Dotted line among the G is not represented two keys, and C ---G is CH 2, C (H) (CH 3) or C (H) (CH 2CH 3).
In another embodiment of the invention, provide the compound of above-mentioned general formula III, wherein C ---Dotted line among the G is represented two keys, and C ---G is C=O, C=S or C=NH, and C ---N (R 6) be C-NH or C-N (C 1-C 4Alkyl).
In another embodiment of the invention, provide the compound of above-mentioned general formula I I, wherein CR 16R 17And CR 4R 6Each is independently selected from-C=O ,-CH 2,-CH (C 1-C 4Alkyl) ,-C (C 1-C 2Alkyl) 2, cyclopropyl ,-CHOH ,-CHOCH 3,-C (OCH 2CH 3) and-C (CH 2OCH 2).
In another embodiment, provide the compound of general formula I I, wherein CR 16R 17Be selected from-CH 2,-CH (C 1-C 4Alkyl) ,-C (C 1-C 2Alkyl) 2, cyclopropyl ,-CHOH and-CHOCH 3, and CR 4R 6Be C=O, CH 2, CH (C 1-C 2Alkyl) or CHOCH 3
In another embodiment of the invention, provide above-mentioned general formula I, II, or the compound of III, wherein R 5Randomly selected from following aryl or heteroaryl replacement: the optional phenyl that replaces, thiazolyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, quinazolyl, quinoxalinyl, pyrazinyl, pyrimidyl, indazolyl, imidazolyl, furyl, benzimidazolyl-, benzofuryl, benzothiazolyl, the benzoisoxazole base, isothiazolyl, pyrazolyl, pyrryl, indyl, pyrrolopyridinyl oxazolyl benzoxazolyl, the diazosulfide base, pyridyl, benzo [1,3] dioxolyl, with 2,3-dihydro-benzo [1,4] dioxine base (dioxinyl).
In another embodiment, R 5Be independently selected from a following 1-4 R 27Replace: C 1-C 4Alkyl ,-O-(C 1-C 4Alkyl), chlorine, bromine ,-CH (CH 3) (OH) ,-C (CH 3) 2(OH) ,-CH (CH 3) (OCH 3) ,-C (CH 3) 2(OCH 3), OCF 3, OCHF 2,-O-cyclopropyl ,-(CH 2-cyclopropyl ,-CH (CF 3) (OH) ,-CH (CF 3) (OCH 3) ,-CH (=O) (CF 3) ,-2-cyclopropyl-1-OH ,-1-cyclopropyl-2-OH ,-1-cyclopropyl-1-NH 2,-O-oxetanyl (oxetanyl) ,-O-tetrahydrofuran base, cyclopropyl and-SCH 3
In another embodiment of the invention, provide above-mentioned general formula I, II, or the compound of III, wherein R 5Be phenyl, pyridyl or pyrimidyl, by two or three R 27Group replaces.In a more specific embodiment, R 5Be phenyl, by two or three R 27Group replaces.
In another embodiment, provide above-mentioned general formula I, II, or the compound of III, wherein R 5Be phenyl, pyridyl or pyrimidyl, selected from two or three following R 27Group replaces: halogen ,-(C 1-C 4Haloalkyl) ,-C (O) R 24,-OR 25,-C (O) NR 24R 25, and C 1-C 10Alkyl, it is randomly selected from a following 1-3 substituting group, is preferably replaced by 1 substituting group: hydroxyl, C 1-C 6Alkoxyl group and NR 24R 25Preferably, each R 27Be independently selected from methyl, ethyl ,-CF 3,-OCH 3,-OCF 3,-C (O) NH 2,-C (O) NHCH 3,-C (O) CF 3,-C (O) CH 3,-CH (OH) CH 3, chlorine, bromine, fluorine ,-OCH 2CH 3,-O-cyclopropyl ,-CH 2NH 2,-CH 2NHCH 3,-CH 2N (CH 3) 2,-CH 2OCH 3, and-CH (OCH 3) CH 3More preferably, each R 27Be independently selected from methyl, ethyl ,-CF 3,-OCH 3,-OCF 3,-C (O) NH 2,-C (O) NHCH 3, chlorine, bromine, fluorine.
In another embodiment, provide general formula I, II, or III, the compound of preferred I, wherein-be phenyl and be independently selected from two or three following substituent R 27Replace: methyl, chlorine ,-OCH 3,-OCF 3, bromine and-C (O) NH 2
In another embodiment of the invention, the compound of above-mentioned general formula I is provided, wherein Z is O, NH or NC (=O) CF 3Preferred Z is O.
In a preferred embodiment of the invention, provide the compound of above-mentioned general formula I, wherein Z is O; B is-NHCHR 1R 2, wherein preferably-C (O) H ,-C (O) (C 1-C 6Alkyl) or-C 1-C 6Alkyl, wherein this C 1-C 6Alkyl is randomly by 1-6 fluorine atom or be independently selected from one or two following R 8Replace :-C 1-C 4Alkyl, hydroxyl and-O-(C 1-C 6Alkyl) and wherein R 2Preferably-C 1-C 12Alkyl randomly comprises 1-3 two keys or triple bond and randomly is selected from fluorine and C by 1-3 1-C 6The substituting group of alkyl replaces; R 5Be phenyl, pyridyl or pyrimidyl, be selected from following R by two or three 27Group replaces: halogen, (C 1-C 4Haloalkyl) ,-C (O) R 24,-OR 25,-C (O) NR 24R 25, and C 1-C 10Alkyl, it randomly is selected from hydroxyl, C 1-C 6Alkoxyl group and-NR 24R 251-3 substituting group, preferred substituting group replaces, and R 4Be-C (O) NR 24R 25-C (O) NR 24R 25R 24And R 25Be independently selected from In a more specific embodiment hydrogen and-C 1-C 4Alkyl.
In another preferred embodiment of the present invention, the compound of general formula I is provided, wherein Z is O; B is-NHCHR 1R 2, wherein-NHCHR 1R 2R 1Preferably-C (O) H ,-C (O) (C 1-C 6Alkyl) or-C 1-C 6Alkyl, wherein this C 1-C 6Alkyl randomly is independently selected from-C by 1-6 fluorine atom or one or two 1-C 4Alkyl, hydroxyl and-O-(C 1-C 6Alkyl) R 8Replace, and wherein-NHCHR 1R 2R 2Preferably-C 1-C 12Alkyl randomly comprises 1-3 two keys or triple bond and randomly is selected from fluorine and C by 1-3 1-C 6The substituting group of alkyl replaces; R 5Be phenyl, pyridyl or pyrimidyl, be selected from following R by two or three 27Group replaces: halogen, (C 1-C 4Haloalkyl) ,-C (O) R 24,-OR 25,-C (O) NR 24R 25, and C 1-C 10Alkyl, it randomly is selected from hydroxyl, C 1-C 6Alkoxyl group and-NR 24R 251-3 substituting group, preferred substituting group replaces, and R 4Be-NR 1R 2, wherein-NR 1R 2R 1C preferably 1-C 6Alkyl, C 3-C 8Cycloalkyl or-(C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl), be more preferably-(C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl) and-NR 1R 2R 2Preferably-C 1-C 12Alkyl randomly comprises two keys of 1-3 or triple bond and randomly by 1-3 fluorine atom replacement.Preferably, B is-N (CH 2-cyclopropyl) (CH 2CH 3) or-N (CH 2-cyclopropyl) (CH 2CF 3).
The example of preferred compound of the present invention is:
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6-methyl-niacinamide;
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-methoxyl group-propyl group amino)-6-methyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-methoxyl group-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2-trifluoromethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide;
2-(4-chloro-2-trifluoromethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1S, 2R-1-ethyl-2-methoxyl group-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1S, 2S-1-ethyl-2-methoxyl group-propyl group amino)-6, N-dimethyl-niacinamide;
And pharmaceutical salts.
Other example of preferred compound of the present invention is:
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-cigarette nitrile (nicotinonitrile);
4-[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-benzamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-methyl sulfenyl (sulfanyl) methyl-propyl group amino)-nicotinic acid methyl ester;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester;
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-cigarette nitrile;
2-(4-chloro-2-trifluoromethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester; With
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester;
And pharmaceutical salts.
Other example of The compounds of this invention is:
2-(4-bromo-2-methoxyl group-phenyl amino)-4-(1-ethyl-propoxy-)-6-methyl-nicotinic acid;
[2-(4-bromo-2-methoxyl group-phenyl amino)-4-(1-ethyl-propoxy-)-6-methyl-pyridin-3-yl]-methyl alcohol;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid;
2-(4-chloro-2,6-dimethyl-phenoxy group-4-(1-methylol-propyl group amino)-6-methylnicotinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-N-ethyl-4-(1-methylol-propyl group amino)-6-methyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6, N-dimethyl-niacinamide;
Cyclopropyl methyl-[2,5,6-trimethylammonium-7-(2,4,6-trimethylammonium-phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine;
Cyclopropyl methyl-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-ethamine;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxycarbonyl-propyl group amino)-6-methyl-nicotinic acid methyl ester;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxycarbonyl-propyl group amino)-6-methyl-nicotinic acid methyl ester;
3,3 ', 6 '-trimethylammonium-2 '-(2,4,6-trimethylammonium-phenoxy group)-3,4,5,6-tetrahydrochysene-2H-[1,4 '] two pyridyl;
2-(4-chloro-2,6-dimethyl-phenoxy group)-6, N-dimethyl-4-(S)-(tetrahydrochysene-furans-3-base is amino)-niacinamide;
[7-(4-bromo-2,6-dimethyl-phenoxy group)-2,5-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-(tetrahydrochysene-furans-3-yl)-amine;
2,5,6-trimethylammonium-4-pyridine alkane-1-base-7-(2,4,6-trimethylammonium-phenyl)-7H-pyrrolo-[2,3-d] pyrimidine;
(2-pyridine alkane-1-base ethyl)-[2,5,6-trimethylammonium-7-(2,4,6-trimethylammonium-phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine;
(tetrahydrochysene-furans-3-yl)-[2,5,6-trimethylammonium-7-(2,4,6-trimethylammonium-phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine;
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-yl)-pyridine-3-carbonyl aldehyde (carbal dehyde) oxime;
[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(2-tetramethyleneimine-1-base-ethyl)-amine;
N-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-2,2,2-three fluoro-N-(2-tetramethyleneimine-1-base-ethyl)-ethanamide;
N2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N1, N1-dimethyl-butane-1,2-diamines;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-methylamino-propyl group amino)-6-methyl-nicotinic acid methyl ester;
[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(3-methyl-butyl)-(2-tetramethyleneimine-1-base-ethyl)-amine;
(3,3-dimethyl-butyl)-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(2-tetramethyleneimine-1-base-ethyl)-amine;
[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-morpholine-4-base-amine;
4-(1-ethyl-propoxy-)-2-(4-methoxyl group-2-methyl-phenyl amino)-6-methyl-nicotinic acid;
2-(4-chloro-2-methyl-phenyl amino)-4-(1-ethyl-propoxy-)-6-methyl-nicotinic acid;
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-pyridin-3-yl oxygen)-nicotinic acid;
N2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N1-pyridin-3-yl methyl-butane-1, the 2-diamines;
N2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N1-thiazol-2-yl methyl-butane-1, the 2-diamines;
2-(2,4-dimethyl-phenyl amino)-4-(1-ethyl-propoxy-)-6-methyl-nicotinic acid;
[2-(4-chloro-2-methyl-phenyl amino)-4-(1-ethyl-propoxy-)-6-methyl-pyridin-3-yl]-methyl alcohol;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-cigarette nitrile;
1-(4-chloro-2-methyl-phenyl)-5-(1-ethyl-propoxy-)-7-methyl isophthalic acid, 4-dihydro-2H-3-Evil-1,8-diaza-naphthalene;
4-(1-ethyl-propyl group amino)-2-methyl-7-(2,4,6-trimethylammonium-phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-5, the 6-diketone;
4-(1-ethyl-propyl group amino)-2-methyl-7-(2,4,6-trimethylammonium-phenyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone;
4-[3-cyano group-4-(1-ethyl-propyl group amino)-6-methyl-pyridine-2-base oxygen]-3-methoxyl group-phenylformic acid;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6-methyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-N-(1-methylol-propyl group)-4-(1-methylol-propyl group amino)-6-methyl-niacinamide;
And the pharmaceutical salts of above-claimed cpd.
The present invention also relates to a kind of pharmaceutical composition that is used for following treatment: (a) its treatment can be by antagonism CRF influence or the promoted obstacle or the state of an illness, include but not limited to induce or promoted obstacle, (b) be selected from the following obstacle or the state of an illness: struvite obstacle such as rheumatic arthritis and osteoarthritis, pain, asthma, psoriasis and allergy by CRF; The universality anxiety disorder, frightened, phobia, comprise social phobia, agoraphobia and specific phobia disease, obsessional idea and behavior disease, stress disorder after the wound, by stress reaction inductive somnopathy, the pain sensation such as fibromyalgia, affective disorder such as melancholia, comprise major depression, single-shot is done depressed, the recurrent depression, child abuse inductive depression, the affective disorder relevant with syndrome before the menstruation, and postpartum depression, depression, bipolar disorder, cyclothymia, chronic tired syndrome, the headache of stress-induced, cancer, irritable bowel syndrome, regional enteritis, spastic colon, postoperative ileus, ulcer, diarrhoea, the fever of stress-induced, the human immunodeficiency virus infection, neurodegenerative disease such as alzheimer's disease, Parkinson's disease and enjoy the court of a feudal ruler disease of pausing, gastrointestinal disease, eating disorder such as appetite stimulator and bulimia nervosa, the hemorrhagic stress reaction, chemical relies on or habituation, comprise for alcohol, Cocaine, heroine, benzodiazepine , or the dependence of other medicines or habituation, medicine or alcohol withdrawal symptom, the phrenoplegia of stress-induced, the normal sick syndrome of thyroid function, the syndrome of inappropriate antidiuresis hormone, obesity, Infertility, wound, spinal cord injuries receptor, the infringement of ischemic neurone, comprise cerebrum ischemia, cerebral hippocampus ischemic for example, the infringement of neurotoxin neurone, epilepsy, apoplexy, immune dysfunction comprises the immune dysfunction of stress-induced, comprise the pig tension syndrome, ox ship fever (bovineshipping fever), horse paroxysmal fibrillation, chicken imprison dysfunction, sheep sheering people animal nervous and dog interacts nervous, muscle spasm, the urinary incontinence, Alzheimer type senile dementia, multi-infarct dementia, amyotrophic lateral sclerosis, hypertension, tachycardia, congestive heart failure, osteoporosis, premature labor, hypoglycemia, with the syndrome X in Mammals that comprises the people or the bird, comprise quantity be effective to treat the such obstacle or the state of an illness according to claim I, II or III compound or its pharmacy acceptable salt and pharmaceutical carrier.
The present invention further comprises a kind of method that is used for following treatment: (a) its treatment can be by antagonism CRF influence or the promoted obstacle or the state of an illness, include but not limited to induce or promoted obstacle, (b) be selected from the following obstacle or the state of an illness: struvite obstacle such as rheumatic arthritis and osteoarthritis, pain, asthma, psoriasis and allergy by CRF; The universality anxiety disorder, frightened, phobia, comprise social phobia, agoraphobia and specific phobia disease, compulsive behavior and idea disease, stress disorder after the wound, by stress reaction inductive somnopathy, the pain sensation such as fibromyalgia, affective disorder such as melancholia, comprise major depression, single-shot is done depressed, the recurrent depression, child abuse inductive depression, the affective disorder relevant with syndrome before the menstruation, and postpartum depression, depression, bipolar disorder, cyclothymia, chronic tired syndrome, the headache of stress-induced, cancer, irritable bowel syndrome, regional enteritis, spastic colon, postoperative ileus, ulcer, diarrhoea, the fever of stress-induced, the human immunodeficiency virus infection, neurodegenerative disease such as alzheimer's disease, Parkinson's disease and enjoy the court of a feudal ruler disease of pausing, gastrointestinal disease, eating disorder such as appetite stimulator and bulimia nervosa, the hemorrhagic stress reaction, chemical relies on or habituation, comprise for alcohol, Cocaine, heroine, benzodiazepine , or the dependence of other medicines or habituation, medicine or alcohol withdrawal symptom, the phrenoplegia of stress-induced, the normal sick syndrome of thyroid function, the syndrome of inappropriate antidiuresis hormone, obesity, Infertility, wound, spinal cord injuries receptor, the infringement of ischemic neurone, comprise cerebrum ischemia, cerebral hippocampus ischemic for example, the infringement of neurotoxin neurone, epilepsy, apoplexy, immune dysfunction comprises the immune dysfunction of stress-induced, comprise the pig tension syndrome, the ox ship fever, horse paroxysmal fibrillation, chicken imprison dysfunction, sheep sheering people animal nervous and dog interacts nervous, muscle spasm, the urinary incontinence, Alzheimer type senile dementia, multi-infarct dementia, amyotrophic lateral sclerosis, hypertension, tachycardia, congestive heart failure, osteoporosis, premature labor, hypoglycemia, with the syndrome X in Mammals that comprises the people or the bird, comprise the obstacle that the object treatment that needs described treatment is such or the general formula I of state of an illness significant quantity, II or III compound or pharmaceutically acceptable salt thereof.
The present invention also is provided for treating the pharmaceutical composition and the method for the state of an illness, comprises that the amount with effective this state of an illness of treatment gives I, II, or the compound of III, and wherein this state of an illness is selected from: a) abnormal circadian rhythm; B) depression wherein is used for the treatment of second kind of depressed compound further, and this is used for the treatment of second kind of depressed compound with regard to the effect of described CRF antagonist, and it postpones to play a role; And c) vomiting.Aforesaid method can be according to the U.S. temporary patent application No.60/151 that submits on August 27th, 1999, and the information that provides in 183 is implemented, document general description use the CRF antagonist that the treatment of the above-mentioned state of an illness and it are incorporated herein by reference in full at this.
General formula I described here, the compound of II and III also can be used for treatment at above-mentioned U.S. series No.09/248, the form disease of the heart failure of describing in 073, and therefore can be prepared into pharmaceutical composition.
The specific form of the abnormal circadian rhythm that can treat according to the present invention or the example of phenomenon comprise, but be not limited to, the time zone of generation changes syndrome, seasonal affective disorder, shift work somnopathy, irregular Sleep-Wake pattern, the delay sleep period syndrome owing to this abnormal circadian rhythm, the sleep period syndrome that shifts to an earlier date or because non-24 hours sleep Arousal disorders of this abnormal circadian rhythm.In addition, in method that is used for the treatment of abnormal circadian rhythm or pharmaceutical composition, general formula I, the compound of II or III can combine with the following second kind of compound that is used for the treatment of somnopathy: for example tachykinin antagenists, the agonist that is used for GABA brain acceptor, metalonergic compound, GABA brain receptor stimulant, 5HT 2Receptor antagonist and D4 receptor binding compounds.Yet, be used for the treatment of other compound of somnopathy or material can with general formula I, the compound combination of II or III.Such method and composition is described in greater detail in aforesaid U.S. temporary patent application No.60/151, in 183.
In another embodiment, this state of an illness is depressed, and the tricyclic antidepressants that this second kind of compound that wherein has the depressed delayed action of treatment is selected from selective serotonin reuptake inhibitor, tricyclic antidepressants, norepinephrine uptake inhibitors, lithium, Bupropion, Sertraline, fluoxetine, trazodone and is selected from imipramine, amitriptyline, Trimipramine, doxepin, Desipramine, nortriptyline, protriptyline, amoxapine, clomipramine, maprotiline and Carbamzepine, and the pharmaceutical salts of above-claimed cpd and ester.
In another embodiment, the state of an illness that treat is vomiting, and this method further comprises the second kind of compound that is used for the treatment of vomiting.The second kind of compound that is used for the treatment of vomiting is selected from but is not limited to tachykinin antagenists, 5HT3 antagonist, gaba agonist and Substance P inhibitor.The vomiting that comprises the more specifically classification of vomiting in the present invention comprises by being selected from the vomiting of the following state of an illness or medicament inductive: pressure change, chemotherapy, radiation, toxin and opium sample pain killer between the gastrointestinal tract dynamia that gestation, vestibular disorder, postoperative disease, gi tract block, reduce, visceral pain, migraine, cranium.
Detailed Description Of The Invention
The compounds of this invention and preparation of compositions method are below described.In following discussion and reaction scheme, unless otherwise indicated, R 1-R 9, R 11, R 12, R 16, R 17, R 19, A, B, G, dotted line and general formula I, II, III, X, XI, XII and IV are following to be defined.
When mentioning alkyl, comprise straight chain and branched-chain alkyl at this.For example, " C 1-C 6Alkyl " comprise and the alkyl of a straight chain and a side chain 1-6 carbon atom include, but is not limited to methyl, ethyl, sec.-propyl, the tertiary butyl and hexyl.
Whenever R 2Or R 5When being heterocyclic group, the connection of group is to pass through carbon atom.
At this whenever the C that mentions " can comprise two keys or triple bond " in above-mentioned definition 1-C 4Alkyl or C 1-C 6During alkyl, be interpreted as in alkyl, having at least two carbon for two keys or triple bond.
When mentioning halogen or halogen, represent fluorine, chlorine, bromine or iodine at this unless otherwise indicated.
Term " treatment (treatment) ", expressions such as " treatments (treating) " comprises slowing down of obstacle progress or reverses, and cures obstacle.These terms also comprise alleviating or lowering of obstacle or state of an illness symptom, even even without removing obstacles truly or the progress self of the state of an illness and obstacle or the state of an illness is not slowed down or reversed.Term terms such as " treatments " also comprises the prophylactic treatment of the obstacle and the state of an illness.
Term " haloalkyl " is represented by one or more halogen atoms, the alkyl that promptly one or more fluorine, bromine, iodine or chlorine atom replace.In addition, understand according to this specification sheets and claim, can be when alkyl by individual as 1-9, when replacing as 9 atoms, when having the carbon atom of enough numbers in alkyl, an optional 1-9 fluorine atom only is a kind of selection.
Unless otherwise indicated, the term in above-mentioned definition " aryl " expression is by removing the organic group of a hydrogen atom derived from aromatic hydrocarbon.The example of aryl is phenyl and naphthyl.
Unless otherwise indicated, term " Heterocyclylalkyl " expression 4-8 unit's monocyclic carbocyclic ring or dicyclo, wherein at least one carbon atom is selected from oxygen, nitrogen, N-(alkyl) or S (O) mAssorted member replace, wherein m is 0,1,2 or 3.Generally speaking, Heterocyclylalkyl comprises four assorted members at the most, preferred 1,2 or 3 assorted member.The Heterocyclylalkyl of The compounds of this invention can randomly comprise 1-3 two key.Term " Heterocyclylalkyl " also comprises heteroaryl groups.The example of heteroaryl comprises thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furyl, benzofuryl, benzothiazolyl, isothiazolyl, benzisothiazole base, benzoisoxazole base, benzimidazolyl-, indyl and benzoxazolyl.Other example of aryl is pyrazolyl, triazolyl, tetrazyl, isoxazolyl, oxazolyl, pyrryl, isoquinolyl, cinnolines base, indazolyl, indolizine base, 2 base, pyridazinyl, triazinyl, pseudoindoyl, purine radicals, oxadiazole base, thiadiazolyl group, furazan base, benzo furazan base, benzimidazole thiophanate phenyl, benzothiazolyl, benzoxazolyl, quinazolyl, quinoxalinyl, naphthyridinyl and furopyridinyl.Preferred heteroaryl is thiazolyl, thienyl, benzothienyl, pyridyl, quinolyl, quinazolyl, quinoxalinyl, pyrazinyl, pyrimidyl, indazolyl, imidazolyl, furyl, benzimidazolyl-, benzofuryl, benzothiazolyl, benzoisoxazole base, isoxazolyl, pyrazolyl, pyrryl, indyl, pyrrolopyridinyl, oxazolyl, benzoxazolyl and diazosulfide base.Other preferred Heterocyclylalkyl be tetrahydrofuran (THF) also, tetrahydropyrans also, morpholino, tetramethyleneimine also, piperidino-(1-position only), piperazine also, [2,2,1]-azabicyclo, [2,2,2]-azabicyclo, [3,3,1]-azabicyclo, rubane also, azetidine also, azetidinone also (azetidinono), oxindole also, glyoxalidine and and pyrrolidinono.Heterocyclylalkyl in the The compounds of this invention can be wherein to be that possible C-connects or N-connects like this.
The compound of general formula I, wherein B is-NR 1R 2,-NHCHR 1R 2,-OCHR 1R 2, or-SCHR 1R 2, and R 3Be methyl, ethyl or chlorine (R hereinafter 19), can be by the compound of general formula I V, wherein D is Cl, and A, R 4, R 5And Z defines referring to as above general formula I, with the compound of Formula B H, wherein B such as above just definition.Be reflected in the solvent, in the presence of alkali, under about 0 °-Yue 230 ℃ temperature, carry out.Suitable solvent is an organic solvent, as tetrahydrofuran (THF) (THF), acetonitrile, dimethyl sulfoxide (DMSO) (DMSO), acetone, C 2-C 15Alkanol, chloroform (CHCl 3), benzene, dimethylbenzene, toluene, tetramethylene sulfone, pyridine, quinoline, 2, ethanamide, two-(C 1-C 2) alkyl ethanamide or 1-Methyl-2-Pyrrolidone.
Compound of Formula I, wherein A is-CR 7With B be-NR 1R 2Or-NHCHR 1R 2The preparation method be two following process.At first, with compound and the excessive R of general formula I V 1NH 2Or NH 3Or equivalent NH 3Precursor is (as NaN 3, nBu 4N +N 3 -Or NH 2OH) under about 75 ℃-Yue 250 ℃ temperature, under the pressure of the about 300psi of about O-, in above-mentioned suitable solvent, react, to form the compound of general formula I, wherein B is-NHR 1,-NH 2,-NH 2OH ,-N 3Can be by means commonly known in the art, as hydrogenation or reduction, with the compound of general formula I, wherein B is-N 3Or-NH 2OH changes into the respective compound of general formula I, and wherein B is-NH 2In the presence of in appropriate base, as two trimethyl silyl acid amides lithiums or sodium, diisopropyl amide lithium or sodium, n-Butyl Lithium or sodium tert-butoxide, in suitable solvent such as THF, diox or methylene dichloride, adopt suitable alkyl halide mutual-through type I compound to carry out alkylation, wherein B is-NHR 1Or-NH 2, obtain the respective compound of general formula I, wherein B is-NR 1R 2Perhaps, carry out the reduction amination of the compound of general formula I, wherein B is-NHR 1Or-NH 2, acidylate for example subsequently with the reaction of borohydride (as sodium borohydride), forms the respective compound of general formula I, and wherein B is-NR 1R 2Or-NHCHR 1R 2
When B is-NR 1R 2Or-NHCHR 1R 2The time, can use excessive BH as reagent and as alkali.Also can use the alkali such as salt of wormwood, the three-(C that are not BH 1-C 6) alkylamine or sodium hydride.Be reflected under the about 75 ℃-Yue 230 ℃ temperature and carry out.When be reflected at alkali, as sodium hydride, C 1-C 4When carrying out under potassium alcoholate or organolithium compound such as n-Butyl Lithium exist, use molar equivalent amine.
When B is-OCHR 1R 2Or-SCHR 1R 2The time, can use can be with the alkali of BH deprotonation, as alkalimetal hydride such as sodium hydride or potassium hydride KH or organo-metallic alkali such as diisopropyl amide sodium, two (trimethyl silyl) acid amides sodium, diisopropyl amide lithium, two (trimethyl silyl) acid amides lithium or C 1-C 4Potassium alcoholate or n-Butyl Lithium.The solvent that uses can be, for example, and tetrahydrofuran (THF), acetonitrile, methyl-sulphoxide, acetone, methylene dichloride, toluene, C 2-C 5Alcohol, chloroform, benzene, dimethylbenzene or 1-Methyl-2-Pyrrolidone, and temperature of reaction can be about 0 ℃-Yue 180 ℃, and preferred about 50 ℃-Yue 80 ℃.
General formula I, the compound of II and III, wherein B such as general formula I, II and III definition, and R 3Define identically, difference is R 3Not methyl or ethyl (R hereinafter 20, it is defined as R 3, difference is that it can not be methyl or ethyl) can prepare in the following way: make general formula I, the compound of II or III, wherein R 3Be chlorine, with general formula R 20The nucleophilic reagent reaction of H is with or without organic or inorganic alkali.Suitable alkali comprises, works as R 20When H is alkanol or alkanethiol, be sodium and sodium hydride; With work as R 20When H was amine, weak base was as salt of wormwood or triethylamine.Can react with tetrabutylammonium, from corresponding compounds, R wherein 20Be chlorine, the compound of preparation general formula I, wherein R 20It is fluorine.Suitable solvent is methyl-sulphoxide, tetrahydrofuran (THF) or methylene dichloride, preferred tetrahydrofuran (THF).
Compound of Formula I as defined above, wherein B is-CR 1R 2R 11,-C (C=CR 2R 12) R 1,-CHR 2OR 12,-CHR 2SR 12, or-C (O) R 2, and R 3Be R 19, can shown in scheme 1, prepare.
Scheme 1
Compound with general formula I V, wherein D is cyano group and A, R4, R5, define with R19 such as above general formula I VA (not shown), it is by corresponding compounds, and wherein D is that chlorine and potassium cyanide or cupric cyanide are at methyl-sulphoxide, 1-Methyl-2-Pyrrolidone, N, prepare in dinethylformamide (DMF) or the ethanamide, with the above-mentioned radicals R that comprises 2Grignard reagent reaction, to form the compound of general formula I A.General formula I A compound with comprise above-mentioned radicals R 1Grignard reagent reaction, the compound of general formula I B is provided.The respective compound of general formula I C, wherein B " be-CR 1R 2R 11, or-C (C=CR 2R 12) R 1Can prepare by usual method.Therefore, IB and acid, as the vitriol oil in acetate, or the Burgess inner salt, as the reaction of hydroxide (carboxyl sulfamyl) triethyl ammonium methyl ester, obtain the compound of general formula I C, wherein B ' is-C (=CR 2R 12) R 1Use palladium/carbon (Pd/C) or platinum dioxide catalyzer to carry out the hydrogenation of compound, wherein B ' is-C (=CR 2R 12) R 1, obtain the compound of general formula I C, wherein B ' is-CR 1R 2The reaction that Compound I B and three fluoridizes diethylamino sulphur or triphenylphosphine/tetracol phenixin provides Compound I C, and wherein B ' is respectively-CR 1R 2F or-CR 1R 2Cl.The reaction of general formula I A compound and sodium borohydride obtains the compound of general formula I, and wherein B is-CHR 2OH.Adopt alkyl halide such as alkiodide, in the presence of alkali such as sodium hydride, at room temperature-CHR 2The alkylation of OH group obtains the compound of general formula I, and wherein B is-CHR 2OR 12
The compound of general formula I I, wherein R 3Be above-mentioned R 19, can be from the compound of general formula I V, wherein R 19, R 4, R 5As above define with A, D is a chlorine, and YR 21Be NH or-CHR 21, R wherein 21Be cyano group or-COO (C 1-C 4Alkyl), following general formula I VB is shown in scheme 2.
Scheme 2
Figure A0180384600381
Can as toluene, benzene, the trimethyl carbinol, acetonitrile and acetone, in the preferred toluene,, prepare the compound of general formula VII, wherein R at suitable solvent by compound and the acid catalyst of heating general formula I VB 4And R 6Respectively do for oneself hydrogen and Y is N.Acid catalyst can be sulfuric acid, hydrochloric acid, tosic acid or methylsulfonic acid, preferred tosic acid.
When the Y among the general formula I VB is CH or N, can use alkali with compound proton deprotonation with general formula I VB.Suitable solvent is tetrahydrofuran (THF), toluene and methylene dichloride, suitable reaction temperature is-78 ℃ to about 100 ℃ approximately, be sodium hydride, potassium hydride KH, potassium tert.-butoxide, two (trimethyl silyl) acid amides lithium and diisopropyl amide lithium or sodium preferably-78 ℃ to about 50 ℃ and suitable alkali.
The compound of general formula VII, wherein R 4And R 6The hydrogen of respectively doing for oneself can adopt alkali such as sodium hydride or organometallic compound such as two (trimethyl silyl) acid amides lithium deprotonation, adopts subsequently to comprise radicals R 4, as R 4L wherein L is a leavings group, as the electrophilic reagent compound of iodine, bromine, methanesulfonates, tosylate, or adopts p-methylphenyl-N-fluoro-N-C 1-C 6Alkyl sulfonamide, iodine, p-nitrophenyl, dimethyl formamide, two (C 1-C 4Alkyl) ketone, formaldehyde, (C 1-C 4Alkyl) aldehyde or bromine quenching are to provide the compound of general formula VII, wherein R 4Be fluorine, chlorine, bromine, iodine, hydroxyl, C 1-C 4Alkyl, S (C 1-C 4Alkyl), CHO, CH (OH) (C 1-C 4Alkyl), CH (OH) (two C 1-C 4Alkyl) or CH 2OH.The other alkylation of hydroxyl or the oxidation of alkylthio cause the compound of general formula VII, wherein R respectively 4Be C 1-C 4Alkoxyl group or SO n(C 1-C 4Alkyl), wherein n is 1 to be 2.The oxidation of general formula VII compound, wherein R 4Be hydroxyl and R 6Be hydrogen, corresponding compounds is provided, wherein CR 4R 6Be C=O, it carries out reduction amination with suitable amine and changes into corresponding compounds, wherein R 4Be amino.The compound of general formula VII, wherein R 4Be that nitro or amino can form in the following way: with the compound of general formula VII, wherein R 4And R 6The both is hydrogen and alkyl nitrite reaction, to form compound, wherein CR 4R 6Be C=NOH, and carry out oxidation or reduce the compound that obtains general formula VII respectively, wherein R 4Be nitro or amine.
Work as R 4And R 6One of when being hydrogen, by adopting reductive agent such as the reduction of lithium aluminum hydride in tetrahydrofuran (THF), the compound of general formula VII can change into corresponding compounds, wherein R 16And R 17The both is a hydrogen.Work as R 4And R 6When both were not hydrogen, identical reduction caused such compound, wherein R 16Be hydrogen and R 17It is hydroxyl.Work as R 17When being hydroxyl, in the presence of sodium hydride, adopt C 1-C 4The alkylation of alkiodide obtains corresponding compounds, wherein R 17Be O (C 1-C 4Alkyl).The compound of general formula VII and organometallic compound are as two (C 1-C 6Alkyl) zinc, C 1-C 6Lithium alkylide or C 1-C 6The reaction of alkyl magnesium bromide obtains the compound of general formula VIII, wherein R 16Or R 17One of be C 1-C 6Alkyl and another are hydroxyls.
General formula VIII compound is the preparation method who is used for compound of Formula I by above-mentioned to the conversion of general formula I IA respective compound.
Can pass through compound of Formula I, wherein R 4Be that amino and Z are NH, with the reaction of phosgene, trichloromethylchloroformate, triphosgene or thiophosgene, the compound of preparation general formula III, wherein G is oxygen or sulphur and R 6Be hydrogen.Be reflected at alkali as three (C 1-C 4Alkyl) under amine exists, in the preferred tetrahydrofuran (THF) of suitable solvent,, preferably under room temperature, carries out at 0 ℃ at-78 ℃ to about 50 ℃.In suitable solvent such as dry tetrahydrofuran, adopt the standard alkylation of these compounds of appropriate base such as sodium hydride, wherein R 6Be hydrogen, provide the compound of general formula III, wherein R 6Be C 1-C 4Alkyl.
Can be in acid as tosic acid (p-TsOH), methylsulfonic acid (MsOH), hydrogen chloride gas (HCl g) or the vitriol oil (H 2SO 4) exist down, in suitable solvent such as toluene, dimethylbenzene, benzene, diox or THF, from about room temperature under about 140 ℃ temperature, preferred about 50 ℃ are arrived about reflux temperature, by the compound of general formula I, R wherein 4Be that amino and Z are NH, with general formula GC (OC 1-C 2Alkyl) 3Compound reaction, the compound of preparation general formula III, wherein G is an alkyl.Perhaps, at alkali such as pyridine, pyridine derivate or three-(C 1-C 4) alkylamine exists down, at suitable solvent such as CH 2Cl 2, CHCl 3, in THF, diox, toluene or the benzene, at about 0 ℃ of reflux temperature to about reaction mixture, preferred about 0 ℃ is arrived under about room temperature the compound of general formula I, wherein R 4Be that amino and Z are NH, can with [G (C=O)] 2O, G (C=O) Cl or G (C=O) F reaction, the cyclisation that under acidic conditions, encircles subsequently (as, pTSOH, MSOH, HCl adopted g, bromize hydrogen gas (HBr g) or the vitriol oil).The cyclisation of ring can be at suitable solvent such as C 1-C 5Carry out among alkyl alcohol, toluene, dimethylbenzene, benzene, diox or the THF.The suitable temp that is used for this reaction can arrive about 140 ℃ for about room temperature.Preferably, temperature of reaction is about 50 ℃-Yue reflux temperature.
The compound of general formula III, wherein G is-O-(C 1-C 2Alkyl) or-OCF 3, can prepare in the following way: with the compound of general formula III, wherein G is oxygen and R 6Be hydrogen, at alkali as three (C 1-C 4Alkyl) amine exists down, with general formula GOSO 2CF 3Compound reacts, or reacts in HMPA or DMF with two trimethyl silyl acid amides lithiums, uses general formula GOSO subsequently 2The compound quenching reaction of OG or G-X, wherein X is bromine, chlorine or SO 3CF 3
The compound of general formula I V, wherein D is chlorine and ZR 5Be NHR 5, can be from compound and the R of general formula V 5NH 2Reaction and prepare:
Figure A0180384600411
Wherein A and R 4As the general formula I definition, and R 19As defined above.Be reflected in tetrahydrofuran (THF) or the methyl-sulphoxide,, carry out under preferred 50 ℃-130 ℃ at about 0 ℃-Yue 150 ℃.Can be by compound and R with general formula V 5OH, R 5SH, R 5NH 2Or R 5CHR 21Reaction, the compound of preparation general formula I V, wherein D is that chlorine and Z are O, S, CHR 21, R wherein 21Be that (=O) R, COOR, wherein R is C for electron deficiency group such as cyano group, C 1-C 4Alkyl, benzoyl or allyl group or SO n -Phenyl, wherein n is 0,1 or 2.Be reflected at following can be with R 5The alkali of ZH deprotonation carries out under existing: as sodium hydride, potassium hydride KH, salt of wormwood, two (trimethyl silyl) acid amides lithium or sodium, dialkyl amide lithium or sodium, (C 1-C 4Alkyl alcohol) sodium or potassium or n-Butyl Lithium are with or without organo-metallic halogenide such as cupric bromide (I), cupric iodide (I) or cupric chloride (I), cupric oxide (II), cupric oxide (I), copper metal and chlorination trialkyltin.The example of operable solvent is tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methylene dichloride, 1-Methyl-2-Pyrrolidone, pyridine, quinoline, N, N-dialkyl acetamides, 2,4,6-trimethylpyridine, N, the N-dialkylformamide, as, N, dinethylformamide (DMF), hexamethylphosphoramide and toluene.Temperature of reaction can be about 0 ℃-Yue 180 ℃ and preferred about 0 ℃-Yue 150 ℃.
The compound of general formula I V, wherein A is CR 7, D is that chlorine and Z are O, S, CHR 21, can prepare in the following way: in suitable solvent such as methylene dichloride or chloroform, under the about 0 ℃-reflux temperature of Yue 100 ℃ and preferably about room temperature-Yue solvent, general formula X compound as follows, wherein R 7With Z such as just definition, reduce with reductive agent such as phosphorus trichloride.
Can be from the compound of general formula X I, as implied above, R wherein 4As definition and R in general formula I 19(that is, methyl or ethyl) as defined above, by with general formula R 5OH, R 5SH or R 5CHR 21Compound reaction, the compound of preparation general formula X.This be reflected at following can be with R 5The alkali of ZH deprotonation carries out under existing: as sodium hydride, potassium hydride KH, two (trimethyl silyl) acid amides lithium, sodium or potassium, dialkyl amide lithium, sodium or potassium, C 1-C 4Sodium alkyl alcohol or potassium or n-Butyl Lithium.Suitable solvent comprises tetrahydrofuran (THF), diox, methyl-sulphoxide, 1-Methyl-2-Pyrrolidone, pyridine, N, N-two-(C 1-C 4Alkyl) ethanamide, ethanamide, N, N-two-(C 1-C 4Alkyl) methane amide, acetonitrile, methylene dichloride, toluene and dimethylbenzene.Suitable reaction temperature can be-78 ℃ to about 150 ℃ and preferred-40 ℃ to about 150 ℃ approximately approximately.
The compound that can prepare general formula X I in the following way: in the mixture of solvent such as methylene dichloride, chloroform, acetate, DMF, methyl alcohol or one or more above-mentioned solvents, from about 0 ℃ to about 100 ℃, arrive under about 60 ℃ temperature with preferred about room temperature, with the respective compound of general formula V, wherein A is-CR 7And R 4And R 19As defined above, with oxygenant such as metachloroperbenzoic acid, peracetic acid or trifluoroacetic acid reaction excessively.
Work as R 4Be that electronics is extracted (withdrawing) group such as NO out 2,-COO (C 1-C 4Alkyl) ,-COOH, CN or-COO (C 1-C 4) during alkyl, the reaction sequence of linked reaction can be put upside down, this is reflected in compound of Formula I synthetic, with B and ZR 5Group is introduced.Can use similar in appearance to above-mentioned those method at ZR 5Introduce the B group before the coupling step.For example, can be by compound and general formula HZR with general formula X II 5Compound reaction, the compound of preparation general formula I, wherein R 4It is the electron deficiency group.Can be in the presence of alkali, by the compound with general formula V, wherein A is CR 7And R 19And R 4As defined above, with Formula B " the compound reaction of H, the compound of preparation general formula X II.
The compound of general formula I V, wherein D is that chlorine and Z are-N (C 1-C 4Alkyl), can prepare in the following way: arrive under the temperature of about room temperature at about-78 ℃ to about 100 ℃ and preferred about 0 ℃, with corresponding compounds, wherein Z is NH, with alkali reaction, adopts C subsequently 1-C 4Alkiodide or bromide quenching.Suitable alkali comprises, for example, and sodium hydride, two (trimethyl silyl) acid amides lithium or sodium, dialkyl amide lithium or sodium and n-Butyl Lithium.Suitable solvent comprises, for example, and tetrahydrofuran (THF), methyl-sulphoxide, toluene, benzene or methylene dichloride.
The compound of general formula I V, wherein D is chlorine, hydroxyl or OP, wherein P is that the standard blocking group and the Z of hydroxyl are-CR 13R 14, can prepare in the following way: above-mentioned can be with the Z group in the presence of the alkali of proton deprotonation, use to comprise R 13Alkylating agent such as R 13I carries out the alkylation of general formula I V compound, and wherein Z is-CHR 21, adopt subsequently to comprise R 14Alkylating agent such as R 14The I quenching.In about 85% phosphoric acid, under about reflux temperature, the compound of heating general formula I V, wherein D is that chlorine or hydrogen and Z are-CH (CN), produces the respective compound of general formula I V, wherein D is that hydroxyl and Z are CH 2Adopt alkali, as be used for R 5The ZH deprotonation above-mentioned those, carry out the deprotonation of general formula I V compound, wherein Z is CH 2, adopt following suitable electrophilic reagent quenching subsequently: as (C 1-C 6Alkyl) iodide, iodine, bromine, Acetyl Chloride 98Min., formaldehyde, acetone, p-methylphenyl-N-fluoro-N-(C 1-C 6Alkyl) sulphonamide, oil of mirbane, nitrous acid C 1-C 6Alkyl ester, oxyethane or dihalide ethane, the respective compound of generation general formula I V, wherein Z is-CHR 13,-CH (OH), cyclopropyl or-C (NOH).Adopt general formula R 14The I alkylating agent, as, more than just described wherein Z be-CHR 13The further alkylation of compound, produce corresponding compounds, wherein Z is C (R 13R 14).
-C (R 5) NOH or-CH (OH) R 5To C (O) R 5Conversion can finish by currently known methods.Wherein Z be-hydrogenation of the compound of C=NOH or reduction provide wherein that Z is-CHNH 2Compound.Use standard organic chemistry, some intermediates can require to protect or separate the selectivity of protection step with the control reaction.
The compound of general formula V, wherein A is that N (compound of general formula VB hereinafter referred to as) or A are CR 7(being the compound of general formula VA) and R 4And R 19Define as general formula I, can prepare in the following way: under about 180 ℃ temperature, preferably under reflux temperature, the compound of general formula VIB and VIA is being with or without under the situation of solvent respectively and 1 equivalent or excessive POCl in about room temperature 3Reaction.The compound of general formula VIA can by in document, describe in known those methods preparation for those skilled in the art.(referring to Helv.ChimicaActa., 25,1306-1313 page or leaf (1942)).
The compound of general formula VIB can prepare in the following way: in the mixture of alcohol (as methyl alcohol) and acetone, under about 50 ℃-Yue 200 ℃ temperature, preferably under reflux temperature, with 1 equivalent R 19C (=NH) (NH 2) HCl salt, 1 equivalent R 4CH (COO-(C 1-C 2Alkyl)) 2React with 2 equivalent alkali such as sodium alkoxide such as sodium methylate. VIA，A＝CR 7VIB，A＝N
When compound of the present invention comprises one or more chiral centre, should understand racemic mixture and all single enantiomorphs and diastereomer and composition thereof of the present invention includes such compound.
The present invention also comprises isotope-labeled compound, they with at general formula I, II, or quote among the III those are identical, replaced by atomic mass or the total mass number atom different but the fact is one or more atoms with atomic mass of in nature, finding usually or total mass number.Can be incorporated into the isotropic substance that isotopic example in the The compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine, as 3H, 11C, 14C, 18F, 123I and 125I.The pharmaceutical salts that comprises the compound of the present invention of above-mentioned isotropic substance and/or other atom isotope and this compound within the scope of the present invention.Compound isotopically labelled of the present invention, for example wherein introduce the radiation isotropic substance as 3H and 14Those of C can be used for medicine and/or the substrate tissue distribution is measured.Because their preparations easily and detectability, contain tritium, promptly 3H and carbon-14, promptly 14The C isotropic substance is particularly preferred. 11C and 18The F isotropic substance be used in particular for PET (positron emission fault roentgenography) and 125The I isotropic substance is used in particular for SPECT (single photon radiation computer tomography), all can be used for being used for the brain imaging.In addition, adopt heavy isotope such as deuterium, promptly 2The replacement of H can provide because some treatment advantage of bringing of greater metabolic stability more, for example dosage requirement of transformation period or reduction in the body of Zeng Jiaing, and so can be preferred in some cases.Generally can replace nonisotopically labelled reagent by the isotope labeling reagent that will obtain easily, prepare general formula I of the present invention, II, or the compound isotopically labelled of III by carrying out disclosed step in scheme and/or in following examples.
Can adopt conventional mode, by adopting the solution or the suspension of the corresponding free alkali of the medicinal acid treatment of chemical equivalent, preparation general formula I, II, or the acid salt of III compound (active compound of the present invention).Can adopt common concentrated or crystallization technique with separated salt.The example of appropriate acid is acetate, lactic acid, succsinic acid, toxilic acid, tartrate, citric acid, gluconic acid, xitix, phenylformic acid, styracin, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, thionamic acid, sulfonic acid such as methylsulfonic acid, Phenylsulfonic acid, tosic acid and relevant acid.
Active compound of the present invention can give separately, or combines with pharmaceutical carrier, gives with single or multiple dosage.Suitable pharmaceutical carrier comprises inert solid diluent or filler, aseptic aqueous solution and various organic solvent.By with general formula I, II, or the compounds of III combine the pharmaceutical composition that forms with their pharmaceutical carrier can various dosage forms, easily give as tablet, powder, lozenge, syrup, injection liquid etc.As needs, these pharmaceutical compositions can comprise other composition, as seasonings, tackiness agent, vehicle etc.Therefore, purpose for oral administration, can adopt the tablet that comprises various vehicle such as Trisodium Citrate, lime carbonate and calcium phosphate, and can be with various disintegrating agents such as starch, methylcellulose gum, Lalgine and some composition silicate, and can use with adhesive polyethylene base pyrrolidone, sucrose, gelatin and gum arabic.In addition, lubricant such as Magnesium Stearate, sodium lauryl sulphate and talcum are generally used for into the tablet purpose.Also can be in the gelatine capsule of soft hard filling, the solids composition that adopts similar type is as weighting agent.The preferred material that is used for this comprises lactose or caramel and high molecular weight polyethylene glycol.When needs aq suspension or elixir are used for oral administration, wherein necessary activeconstituents can with various sweeting agents or seasonings, coloring material or dyestuff and, as needs, emulsifying agent or suspension agent combination, and can use with thinner such as water, ethanol, propylene glycol, glycerine and its binding substances.
For parenteral admin, can adopt the solution that contains active compound of the present invention or its pharmaceutical salts in sesame oil or peanut oil, aqueous propylene glycol or in aseptic aqueous solution.The aqueous solution as needs should cushion suitably with salt solution that adopts capacity or glucose and at first liquid diluting be become isoosmotic.These specific aqueous solution are particularly suitable for intravenously, intramuscular, subcutaneous and intraperitoneal administration.All all are obtainable easily by standard technique well known by persons skilled in the art for the sterile aqueous media that adopts.
General formula I, II, or the effective dose of the salt of III compound and they depends on required route of administration and as factors such as patient's age and body weight, and known such as the doctor.Dosage also depends on the specified disease that will treat.For example, for stress reaction inductive disease, struvite obstacle, alzheimer's disease, gastrointestinal disorder, anorexia nervosa, hemorrhagic stress reaction and medicine and alcohol withdrawal symptom, every day, dosage was generally the about 50mg/kg of about 0.1-weight in patients to be treated.Those skilled in the art can be by with reference to relating to particular obstacle to be treated or state of an illness accessory text is determined effective dose.
The method that can be used for the CRF antagonistic activity of definite active compound of the present invention and pharmaceutical salts thereof is described in Endocrinology, and 116,1653-1659 (1985) and Peptides, 10, among the 179-188 (1985).Be expressed as IC 50The value general formula I, II and III compound be generally about 0.5 nanomole-Yue 10 micromoles in conjunction with activity.
By following embodiment the present invention is described.Yet, should be appreciated that the present invention is not limited to the concrete details of these embodiment.Fusing point is uncorrected.Proton magnetic resonance (PMR) spectrum ( 1HNMR) and C 13NMR (Nuclear Magnetic Resonance) spectrum (C 13NMR) measuring is at deuterochloroform (CDCl 3) in solution carry out, the peak position is expressed as the 1000000/umber (ppm) apart from the downfield of tetramethylsilane (TMS).Peak shape is expressed as follows: s, and unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; B, broad peak.
Use following abbreviation in an embodiment: the Ph=phenyl; The iPr=sec.-propyl; The HRMS=high resolution mass spec.
Embodiment 1
By similar in appearance to following method, reaction by (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(alkyl-or dialkyl group)-amine and fortified phenol, be prepared as follows compound: to (2-chloro-6-methyl-3-nitro-pyridin-4-yl) in dry THF-(alkyl-or dialkyl group)-amine (1mmol) and 2,4, in the mixture of 6-pseudocuminol (1mmol), add potassium tert.-butoxide (1mmol) and the mixture that obtains at room temperature stirred up to all starting raw materials and run out of.Mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer is dry and concentrated to obtain title compound after the purifying by silica gel column chromatography:
2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-3-nitro-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.69(，1H)，6.289s，1H)，3.65-3.80(m，2H)，3.60m，1H)，2.12(s，3H)，2.08(s，6H)，1.8(brs，1H)，1.5-1.8(m，2H)，1.01(t，3H)ppm.
(1-methoxymethyl-propyl group)-[6-methyl-3-nitro-2-(4-trifluoromethoxy-phenoxy group)-pyridin-4-yl]-amine
Yellow solid 75-76 ℃, ultimate analysis, C 18H 20N 3O 5F 3, calculated value C52.05; H, 4.85; N, 10.12; Measured value, C, 52.14; H, 5.04; N, 10.13
2-(2-amino-4,6-two chloro-phenoxy groups)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?9.55(d，1H)，7.23(d，1H)，7.00(d，1H)，6.05(s，1H)，3.69(m，1H)，3.49(m，2H)，3.38(s，3H)，2.35(s，3H)，1.78(m，1H)，1.65(m，1H)，0.99(t，3H)ppm.
3-methoxyl group-2-[4-(1-methoxymethyl-propyl group amino)-6-methyl-3-nitro-2-base oxygen]-phenyl aldehyde
Yellow solid 126.5-130.5 ℃, ultimate analysis, C 19H 23N 3O 6, calculated value C58.60; H, 5.95; N, 10.79; Measured value, C, 58.45; H, 6.11; N, 10.32
[2-(2,6-two bromo-4-trifluoromethoxy-phenoxy groups)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
Yellow solid 1H NMR (CDCl 3) d 8.00 (d, 1H), 7.49 (, 2H), 6.35 (s, 1H), 3.64 (m, 1H), 3.53 (m, 2H), 3.43 (s, 3H), 2.20 (s, 3H), 1.6-1.9 (m, 4H), 1.04 (t, 3H) ppm.
[2-(2-bromo-4-chloro-6-methoxyl group-phenoxy group)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
Yellow solid 111.8-113.6 ℃, ultimate analysis, C 15H 21N 3O 5BrCl, calculated value C, 45.54; H, 4.46; N, 8.85; Measured value, C, 45.94; H, 4.32; N, 8.68
[2-(2,4-two chloro-phenoxy groups)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.83(d，1H)，7.46(d，1H)，7.30(dd，1H)，7.15(dd，1H)，6.33(s，1H)，3.65(m，1H)，3.51(m，2H)，?3.42(s，3H)，2.21(s，3H)，1.82(m，1H)，1.66(m，1H)，1.03(t，3H)ppm.
[2-(2-bromo-6-chloro-4-methoxyl group-phenoxy group)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.88(d，1H)，7.04(d，1H)，6.93(d，1H)，6.27(s，1H)，3.79(s，3H)，3.60(m，1H)，3.4-3.5(m，2H)，3.38(s，3H)，2.15(s，3H)，1.78(m，1H)，1.64(m，1H)，0.99(t，3H)
(1-methoxymethyl-propyl group)-[6-methyl-3-nitro-2-(2,4,6-trimethoxy-phenoxy group)-pyridin-4-yl]-amine
Mp.126.8-129.5 ℃, ultimate analysis, C 20H 27N 3O 7Calculated value C, 57.00; H, 6.46; N, 9.97; Measured value, C, 56.94; H, 6.85; N, 9.66.
Embodiment 2
2-chloro-N-[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-ethanamide
Under 0 ℃, to N-4-(1-ethyl-propyl group)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-and pyridine-3, (250mg is 0.763mmol) in the solution in dry THF for the 4-diamines, add acetyl chloride chlorine (80mg, 0.763mmol) and triethylamine (77mg, 0.763mmol).The mixture that obtains is warmed up to the stirring 1hr of room temperature.Mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer by anhydrous sodium sulfate drying, is filtered, be concentrated to drying, obtain being the solid title compound.Solid is obtained 280mg (91%) tawny crystal, mp.152-154 ℃ by silica gel chromatography.
1H?NMR(CDCl 3)d?8.07(brs，1H)，6.88(s，2H)，6.16(s，1H)，4.75(m，1H)，4.25(s，2H)，3.33(m，1H)，2.30(s，3H)，2.18(s，3H)，2.08(s，6H)，1.4-1.75(m，4H)，0.97(t，6H)ppm.
By being prepared as follows compound similar in appearance to the method in aforementioned paragraphs:
3-chloro-N-[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-propionic acid amide
Brown solid 183-185 ℃, ultimate analysis, C 23H 32ClN 3O 2Calculated value C, 66.09; H, 7.72; N, 10.05; Measured value, C, 66.27; H, 7.87; N, 9.99.
2-chloro-N-[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-propionic acid amide
Mp.170-172 ℃, ultimate analysis, C 23H 32ClN 3O 2Calculated value C, 66.09; H, 7.72; N, 10.05; Measured value, C, 66.20; H, 7.52; N, 10.09.
Embodiment 3
N3-allyl group-N4-(1-ethyl-propyl group)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-3, the 4-diamines
Under-78 ℃, to the N-4-in dry THF (1-ethyl-propyl group)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-3, the 4-diamines (500mg, 1.52mmol) add in the solution two (trimethyl silyl) acid amides lithiums of 1M in THF (1.6ml, 1.6mmol).After-78 ℃ were stirred 10min down, (0.13ml 1.52mmol) and with the mixture that obtains stirred 20min under this temperature, be heated to ambient temperature overnight then to add allyl bromide 98.Mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer by anhydrous sodium sulfate drying, is filtered, be concentrated to drying, obtain being green-blue buttery title compound.5% ethyl acetate of use in hexane obtains yellow crystals with oil by silica gel chromatography, mp.86-88 ℃ as eluent.
1H?NMR(CDCl 3)d?6.87(s，2H)，6.0(m，2H)，5.2-5.35(m，2H)，4.8(d，1H)，3.54(d，2H)，3.3(m，1H)，3.05(s，1H)，2.30(s，3H)，2.14(s，3H)，2.09(s，6H)，1.4-1.6(m，4H)，0.96(t，6H)ppm.
Be prepared as follows compound by similar methods:
N3-(3-chloro-propyl group)-N4-(1-ethyl-propyl group)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-3, the 4-diamines
1H?NMR(CDCl 3)d?6.85(s，2H)，6.05(s，1H)，4.9(d，1H)，3.8(m，2H)，?3.3(m，1H)，3.1(m，2H)，2.3(s，3H)，2.159s，3H)，2.04(s，6H)，1.79m，2H)，1.5(m，2H)，1.0(m，6H)ppm.
N4-(1-ethyl-propyl group)-6-methyl-N3-the third-1,2-dialkylene-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-3,4-diamines
1H?NMR(CDCl 3)d?8.93(d，1H)，6.86(s，2H)，6.66(m，1H)，6.09(s，1H)，5.4-5.6(m，2H)，5.54(d，1H)，3.27(m，1H)，2.27(s，3H)，2.12(s，3H)，2.05(s，6H)，1.6(m，4H)，0.94(t，6H)ppm.
Embodiment 4
2-[3-amino-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
Under refluxing, with 2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-3-nitro-pyridine-4-(S)-Ji amino]-Ding-1-alcohol (120mg) and Fe (73mg) be at 1 of 12ml: 1AcOH: H 2Mixture heating up 2hr among the O.Reaction mixture is concentrated to drying.Resistates is adopted the water quenching, be basified to pH12 and pass through the filtration of C salt.Filtrate is adopted chloroform extraction.Organic layer is adopted the salt water washing, the dry and concentrated title compound that obtains to yellow solid.Use 1: 1EtOAc: hexane obtains white solid with solid by silica gel chromatography as eluent, mp.161-162 ℃.
1H?NMR(CDCl 3)d?7.03(s，2H)，6.15(s，1H)，3.75(m，2H)，3.47(m，1H)，2.25(brs，3H)，2.08(s，6H)，1.5-1.8(m，2H)，0.98t，3H)ppm
Embodiment 5
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
Under 120 ℃, (77mg is 0.226mmol) with the mixture heating up 4hr of 1-ethyl-propyl group-amine in DMSO with 4-chloro-6-methyl-2-(4-chloro-2,6-dimethyl-phenoxy group)-nicotinic acid methyl ester.Mixture is adopted saturated ammonium chloride, water, salt solution quenching and adopts ethyl acetate extraction.With the dry and concentrated 140mg yellow solid that obtains of organic layer.
1HNMR(CDCl 3)d?8.10(d，1H)，7.03(s，2H)，6.09(s，1H)，3.88(s，3H)，3.35(m，1H)，2.10(s，3H)，2.08(s，6H)，1.5-1.7(m，4H)，0.96(t，6H)ppm.
Embodiment 6
2-(4-bromo-2,6-dimethyl-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
Under 120 ℃, with 4-chloro-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy group)-nicotinic acid methyl ester and the mixture heating up 16hr of 1-ethyl-propyl group-amine in DMSO.Mixture is adopted water, salt solution quenching and adopts ethyl acetate extraction.The organic layer drying is concentrated to drying.The use hexane as eluent, obtains resistates the title compound of white solid to 3% ethyl acetate in hexane by silica gel chromatography.
1H?NMR(CDCl 3)d?8.1(d，1H)，7.18(s，2H)，6.08(s，1H)，3.87(s，3H).3.35(m，1H)，2.10(s，3H)，2.08(s，6H)，1.4-1.7(m，4H)，0.96(t，6H)ppm.
Embodiment 7
4-(1-ethyl-Propargyl amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
Under 130 ℃, 4-chloro-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester and the mixture heating up of 1-ethyl-propyl group-amine in DMSO are spent the night.Mixture is adopted water, salt solution quenching and adopts ethyl acetate extraction.The organic layer drying is concentrated to drying.Resistates is obtained title compound by silica gel chromatography.
1H?NMR(CDCl 3)d?8.26(d，1H)，6.87(s，2H)，6.26(s，1H)，4.11(m，1H)，3.87(s，3H)，2.324(m，1H)，2.30(s，3H)，2.17s，3H)，2.08(s，6H)，1.92(q，2H)，1.16(t，3H)ppm.
Embodiment 8
4-(s)-(1-methylol-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
In 130 ℃ of oil baths, with 4-chloro-2-(2,4,6-trimethylammonium-phenoxy group)-6-methyl-nicotinic acid methyl ester (500mg, 1.56mmol) and (S)-2-amino-1-butanols (696mg, 7.82mmol) the mixture heating up 24hr in DMSO.With mixture cool to room temperature and employing water quenching and employing ethyl acetate extraction.Organic layer is separated, adopt water washing,, filter, and be concentrated to drying and obtain the crude product of 610mg for oil by anhydrous sodium sulfate drying.30% ethyl acetate of use in hexane obtains title compound with oil by silica gel chromatography as eluent.Ultimate analysis calculated value C 21H 28N 2O 4.1/2H 2O:C, 66.11; H, 7.66; N, 7.34; Measured value: C, 66.27; H, 7.60; N, 7.21.
Embodiment 9
4-(1-ethyl-2-hydroxyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
In 130 ℃ of oil baths, (250mg is 0.78mmol) with 3-amino-penta-2-alcohol (320mg, 3.13mmol) the mixture heating up 24hr in DMSO with 4-chloro-2-(2,4,6-trimethylammonium-phenoxy group)-6-methyl-nicotinic acid methyl ester.With mixture cool to room temperature and employing water quenching and employing ethyl acetate extraction.Organic layer is separated, adopt water washing,, filter, be concentrated to drying and obtain the crude product of 280mg for oil by anhydrous sodium sulfate drying.20% ethyl acetate of use in hexane be as eluent, oil obtained title compound into yellow solid by silica gel chromatography, mp116-120 ℃.
1H?NMR(CDCl 3)d?8.17(m，1H)，6.87(s，2H)，6.21&6.14(two?s，1H)，3.88(s，3H)，3.8-4.0(m，2H)，3.5(m，1H)，3.3(m，1H)，2.30(s，3H)，2.12(s，3H)，2.09(s，6H)，1.8(d，1H)，1.5-1.8(m，2H)，1.26(d，3H)，0.99(t，3H)ppm.
Embodiment 10
2-(4-bromo-2,6-dimethyl-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester
In 130 ℃ of oil baths, with 4-chloro-2-(4-bromo-2,6-trimethylammonium-phenoxy group)-6-methyl-nicotinic acid methyl ester (850mg) and (S)-the 2-amino-mixture heating up 24hr of 1-butanols in DMSO.With mixture cool to room temperature and employing water quenching and employing ethyl acetate extraction.Organic layer is separated, adopt water washing,, filter, be concentrated to drying and obtain the crude product of 764mg for oil by anhydrous sodium sulfate drying.Oil is obtained title compound by silica gel chromatography.1H?NMR(CDCl 3)d?8.15(d，1H)，7.16(s，2H)，6.18(s，1H)，3.86(s，3H)，3.72(m，1H)，3.70(m，1H)，3.54(m，1H)，2.10(s，3H)，2.06(s，6H)，1.5-1.8(m，2H)，1.00(t，3H)ppm.
Embodiment 11
2-(4-bromo-2,6-dimethyl-phenoxy group)-4-(S)-(1-methoxymethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
In 130 ℃ of oil baths, with 4-chloro-2-(4-bromo-2,6-trimethylammonium-phenoxy group)-6-methyl-nicotinic acid methyl ester and the mixture heating up 24hr of 1-methoxymethyl-propylamine in DMSO.With mixture cool to room temperature and employing water quenching and employing ethyl acetate extraction.Organic layer is separated, adopt water washing,, filter, be concentrated to drying and obtain crude product by anhydrous sodium sulfate drying.Crude product is obtained title compound by silica gel chromatography.
Embodiment 12
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester
Under 130 ℃, with 4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-and 6-methyl-nicotinic acid methyl ester (9.000g, 26.45mmol) and (S)-the 2-amino-mixture heating up 2hr of 1-butanols (12.7ml) in 1-Methyl-2-Pyrrolidone, under 100 ℃, spend the night then.To dilute with the employing ethyl acetate in mixture cool to room temperature and the impouring frozen water.Organic layer is separated, adopt water washing,, filter, be concentrated to drying and obtain the crude product that 13.6g is a light yellow oil by anhydrous sodium sulfate drying.As eluent, it is the foamed title compound of white glass that oil is obtained 6.6839g (64%) by silica gel chromatography to the use chloroform to 2%MeOH in chloroform.Adopt the hexane development to obtain white solid glass foam.Solid is obtained white crystal from the diisopropyl ether recrystallization.Mp 122.5-124 ℃ of ultimate analysis calculated value C 20H 25ClN 2O 4: C, 61.14; H, 6.41; N, 7.13; Measured value: C, 60.98; H, 6.43; N, 6.95.
Embodiment 13
2-(4-chloro-2,6-dimethoxy-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester
Under 130 ℃, 4-chloro-2-(4-chloro-2-methoxyl group-phenoxy group)-6-methyl-nicotinic acid methyl ester and (the S)-2-amino-mixture heating up of 1-butanols in 1-Methyl-2-Pyrrolidone spent the night.To dilute with the employing ethyl acetate in mixture cool to room temperature and the impouring frozen water.Organic layer is separated, adopt water washing,, filter, be concentrated to drying by anhydrous sodium sulfate drying.Resistates is obtained being the solid title compound by silica gel chromatography.Mp.92.8-93.8 ℃, ultimate analysis C 19H 23N 2O 5Cl: calculated value, C, 57.80; H, 5.87; 7.09; Measured value, C, 57.70; H, 5.89; 7.02.
Embodiment 14
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-hydroxyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
In 130 ℃ of oil baths, (500mg is 1.47mmol) with 3-amino-penta-2-alcohol (758mg, 7.35mmol) the mixture heating up 24hr in 1-Methyl-2-Pyrrolidone with 4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester.With mixture cool to room temperature and employing water quenching and employing ethyl acetate extraction.Organic layer is separated, adopt water washing,, filter, be concentrated to drying and obtain oil by anhydrous sodium sulfate drying.20% ethyl acetate of use in hexane be as eluent, oil obtained title compound into white crystal by silica gel chromatography, mp133-135 ℃.
1H NMR (CDCl 3) d 8.19 (m, 1H), 7.00 (s, 2H), 6.20﹠amp; 6.14 (two cover s, 1H), 3.8-3.9 (m, 1H), 3.86 (s, 3H), 3.3﹠amp; 3.5 (two cover m, 1H), 2.07 (s, 3H), 2.06 (s, 6H), 1.75 (m, 1H), 1.55 (m, 1H), 1.24 (d, 3H), 0.96 (t, 3H) ppm.
Embodiment 15
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-methoxyl group-propyl group amino)-6-methyl-nicotinic acid methyl ester
(50mg 0.123mmol) adds NaH and stir 20min in the solution to the 2-in dry THF (4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-hydroxyl-propyl group amino)-6-methyl-nicotinic acid methyl ester.Add excessive MeI and the mixture that obtains at room temperature stirred and spend the night.With mixture cool to room temperature and employing water quenching and employing ethyl acetate extraction.Organic layer is separated, adopt water washing,, filter, be concentrated to drying and obtain oil by anhydrous sodium sulfate drying.20% ethyl acetate of use in hexane obtains be clarification buttery title compound with oil by silica gel chromatography as eluent.
1H NMR (CDCl 3) d 8.20 (d, 1H), 7.00 (s, 2H), 6.14﹠amp; 6.10 (two cover s, 1H), 3.859s, 3H), 3.47 (m, 1H), 3.39﹠amp; 3.37 (two cover s, 3H), 2.08 (s, 3H), 2.06 (s, 6H), 1.75 (m, 1H), 1.58 (m, 1H), 1.14 (t, 3H), 0.95 (t, 3H) ppm.
Embodiment 16
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-oxo-propyl group amino)-6-methyl-nicotinic acid methyl ester
Dess-Martin oxidation by 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-hydroxyl-propyl group amino)-6-methyl-nicotinic acid methyl ester prepares title compound.After silica gel column chromatography, obtain white solid.1H?NMR(CDCl 3)d8.6(d，1H)，7.01(s，2H)，5.899s，1H)，3.9-4.0(m，1H)，3.90(s，3H)，2.17(s，3H)，2.07(s，3H)，2.05(s，3H)，1.859m，1H)，1.93(m，1H)，1.00(t，3H)ppm.
Embodiment 17
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-formyl radical-propyl group amino)-6-methyl-nicotinic acid methyl ester
Dess-Martin oxidation by 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester prepares title compound.After column chromatography, obtain title compound.1H?NMR(CDCl 3)9.54(d，1H)，8.56(d，1H)，7.01(s，2H)，5.93(s，1H)，3.92(m，1H)，3.89(s，3H)，2.08(s，3H)，2.05(s，6H)，1.05(t，3H)ppm.
Embodiment 18
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(4-ethyl-2-oxo-oxazolidines-3-yl)-6-methyl-nicotinic acid methyl ester
With 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester (106mg, 0.27mmol), triphosgene (27mg, 0.090mmol), (27mg, 0.27mmol) mixture in dry THF at room temperature stirs 2hr to triethylamine.Mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer is separated, adopt water washing, by anhydrous sodium sulfate drying, filter, being concentrated to drying, to obtain 13.6g be the foamed crude product of white glass.Adopt hexane/ether development to obtain white solid foam.Mp.144-145.5 ℃, ultimate analysis C 21H 23ClN 2O 5Calculated value: C, 60.22; H, 5.53; N, 6.69; Measured value: C, 60.10, H, 5.79; N, 6.66.
Embodiment 19
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-[(2-hydroxyl-ethylamino)-methyl]-propyl group amino }-6-methyl-nicotinic acid methyl ester
In 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-formyl radical-propyl group the amino)-solution of 6-methyl-nicotinic acid methyl ester in ethylene dichloride, add 2-amino-ethanol, sodium cyanoborohydride, acetate, anhydrous sodium sulphate.The mixture that obtains is heated and cooled to room temperature under refluxing.Mixture is adopted the water quenching and adopts chloroform extraction.Organic layer is separated, adopt water washing,, filter, be concentrated to drying by anhydrous sodium sulfate drying.After chromatogram, obtain to be the foamed title compound of white glass.1H?NMR(CDCl 3)d?8.3(d，1H)，7.0(s，2H)，6.1(s，1H)，3.9(s，3H)，3.64(m，2H)，3.57(m，1H)，2.90(m，2H)，2.83(m，2H)，2.5(brs，2H)，2.09(s，3H)，2.06(s，6H)，1.65(m，2H)，0.97(t，3H)ppm.
Embodiment 20
4-[ethyl-(2-hydroxyl-ethyl)-amino]-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
Under 130 ℃, 4-chloro-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester and the mixture heating up of 1-ethyl-propyl group-amine in 1-Methyl-2-Pyrrolidone are run out of up to starting raw material.Mixture is adopted water, salt solution quenching and adopts ethyl acetate extraction.The organic layer drying is concentrated to drying.Resistates is obtained title compound by silica gel chromatography.1H?NMR(CDCl 3)d?6.85(s，2H)，6.40(s，1H)，3.88(s，3H)，3.73(t，2H)，3.43(t，2H)，3.31(q，2H)，2.27(s，3H)，2.22(s，3H)，2.06(s，6H)，1.15(t，3H)ppm.
Embodiment 21
4-[ethyl-(2-mesyloxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
With 4-[ethyl-(2-hydroxyl-ethyl)-amino]-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester, methylsulfonyl chloride and triethylamine at room temperature stir up to all starting raw materials at the mixture of methylene dichloride and run out of.Mixture is adopted water, salt solution quenching and adopts ethyl acetate extraction.The organic layer drying is concentrated to drying.Resistates is obtained title compound by silica gel chromatography.1H?NMR(CDCl 3)d?6.83(s，2H)，6.25(s，1H)，4.34(t，2H)，3.86(s，3H)，3.6(t，2H)，3.38(t，2H)，3.09s，3H)，2.25(s，3H)，2.20(s，3H)，2.04(s，6H)，1.18(t，3H)ppm.
Embodiment 22
4-[(2-hydroxyl-ethyl)-thiophene-2-ylmethyl-amino]-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
Under 130 ℃, with 4-chloro-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester and 2-[(thiophene-2-ylmethyl)-amino]-mixture heating up of ethanol in 1-Methyl-2-Pyrrolidone spend the night.Mixture is adopted water, salt solution quenching and adopts ethyl acetate extraction.The organic layer drying is concentrated to drying.Resistates is obtained title compound by silica gel chromatography.1H?NMR(CDCl 3)d?7.22(m，1H)，6.94m，2H)，6.84(s，2H)，6.44(s，1H)，4.52(s，2H)，3.91(s，3H)，3.679t，2H)，3.369t，2H)，2.279s，3H)，2.20(s，3H)，2.07(s，6H)ppm.
Embodiment 23
By similar in appearance to the method in embodiment 5, adopt suitable 4-chloro-6-methyl-2-(replacement-phenoxy group)-nicotinic acid alkyl esters and suitable alkyl-or dialkyl group-amine begin, be prepared as follows compound.
4-(2,2-dimethyl-4-phenyl-[1,3] diox-5-base-amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.71(d，2H)，7,1-7.4(m，5H)，6.82(s，2H)，5.55(s，1H)，5.229s，1H)，4.29(d，1H)，3.97(d，1H)，3.869s，3H)，3.61(d，1H)，2.25(s，3H)，2.01(s，6H)，1.91(s，3H)，1.65(s，3H)，1.61(s，3H)ppm.
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6-methyl-Nikithan
1H?NMR(CDCl 3)d?8.01(d，1H)，7.02(s，2H)，6.17(s，1H)，4.33(q，2H)，3.71(m，1H)，3.66(m，1H)，3.54m，1H)，2.10(s，3H)，2.07(s，6H)，1.5-1.8(m，2H)，1.33(t，3H)，1.00(t，3H)ppm.
4-[ethyl-(2-methoxyl group-ethyl)-amino]-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?6.83(s，2H)，6.19(s，1H)，3.869s，3H)，3.35-3.6(m，4H)，3.35(s，3H)，2.26(s，3H)，2.15(s，3H)，2.06(s，6H)，1.179t，3H)ppm.
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S, R)-﹠amp; (S, S)-(1-ethyl-2-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.2(d，1H)，7.01(s2H)，6.20(s，0.2H)，6.15(s，0.8H)，3.92(m，1H)，3.87(s，3H)，3.48(m，0.2H)，3.31(m，0.8H)，2.08(s，3H)，2.06(s，6H)，1.5-1.8(m，2H)，1.25(d，3H)，0.96(t，3H)ppm.
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(R)-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)8.12(d，1H)，7.00(s，2H)，6.16(s，1H)，3.85(s，3H)，3.6-3.8(m，2H)，3.53(m，1H)，2.08(s，3H)，2.05(s，6H)，1.5-1.8(m，2H)，0.98(t，3H)ppm.
4-(2-hydroxyl-1-methylol-ethylamino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.44(d，1H)，6.84(s，2H)，6.17(s，1H)，3.8-4.0(m，4H)，3.85(s，3H)，3.70(m，1H)，2.60(s，3H)，2.27(s，3H)，2.11(s，2H)，2.05(s，6H)ppm.
4-(2-methoxyl group-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.38(d，1H)，6.88(s，2H)，6.18(s，1H)，3.88(s，3H)，3.78(m，1H)，3.56(m，2H)，3.44(s，6H)，2.31(s，3H)，2.15(s，3H)，2.09(s，6H)ppm.
4-(1-methylol-2-methoxyl group-ethylamino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.44(d，1H)，6.88(s，2H)，6.21(s，1H)，3.89(s，3H)，3.80(m，1H)，3.5-3.7(m，2H)，3.45(s，3H)，2.31(s，3H)，2.16(s，3H)，2.09(s，6H)ppm.
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-hydroxyl-butyl amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.34(d，1H)，7.069s，2H)，6.16(s，1H)，3.91(s，3H)，3.70(m，1H)，3.5(m，1H)，2.13(s，3H)，2.11(s，6H)，1.5-1.9(m，4H)，1.01(m，6H)ppm.
Embodiment 24
[2-(4-chloro-2,6-dimethyl-phenyl amino)-4-(1-ethyl-propyl group amino)-6-methyl-pyridin-3-yl]-methyl alcohol
Under-78 ℃, (130mg 0.332mmol) stirs 10min with the mixture of excessive 1M diisobutylaluminium hydride in dry THF, is warmed up to room temperature then with 4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester.Mixture is adopted the methyl alcohol quenching and at room temperature stirs 20min, filter and adopt methyl alcohol and chloroform washing by C salt.Filtrate is concentrated to drying.Resistates is obtained title compound by silica gel chromatography.
1HNMR(CDCl 3)d?7.03(s，2H)，6.11(s，1H)，5.03(d，1H)，4.96(s，2H)，3.32(m，1H)，2.14(s，3H)，2.07(s，6H)，1.4-1.7(m，4H)，0.96(t，6H)ppm.
[2-(4-bromo-2,6-dimethyl-phenyl amino)-4-(1-ethyl-propyl group amino)-6-methyl-pyridin-3-yl]-methyl alcohol
Prepare title compound by method similar in appearance to aforementioned paragraphs.
1H?NMR(CDCl 3)d?7.18(s，2H)，6.11(s，1H)，5.05(d，1H)，4.91(d，2H)，3.31(m，1H)，2.14(s，3H)，2.07(s，6H)，1.4-1.7(m，4H)，0.96(t，6H)ppm.
Embodiment 25
2-[3-methylol-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
Under refluxing, with 4-(S)-(1-methylol-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid methyl ester and 1M lithium aluminum hydride and the mixture heating up of aluminum chloride in THF.With mixture cooling with adopt water, 2N NaOH, water quenching and at room temperature stir 10min then.Form white solid and white solid is filtered employing THF washing by C salt.After column chromatography, filtrate is concentrated to drying obtains title compound into white solid.
Mp.135-137 ℃; Ultimate analysis C 20H 28N 2O 3Calculated value C, 69.74; H, 8.19; N, 8.13; Measured value C, 69.42; H, 8.34; N, 7.95
By similar in appearance to the method in aforementioned paragraphs, adopt corresponding ester to begin and make it reaction with lithium aluminum hydride and aluminum chloride, be prepared as follows compound.
3-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methylol-6-methyl-pyridin-4-yl amino]-penta-2-alcohol
Mp.180-182 ℃ of .1H NMR (CDCl 3) 7.0 (s, 2H), 6.18﹠amp; 6.15 (two cover s, 1H), 5.1 and 5.22 (m, 1H), 4.92 (m, 2H), 3.80-4.0 (m, 1H), 3.20-3.5 (m, 1H), 2.11 (s, 3H), 2.04 (s, 6H), 1.4-1.8 (m, 2H), 1.23 (m, 3H), 0.98 (m, 3H) ppm.
2-[2-(2,6-dimethyl-phenoxy group)-3-methylol-6-methyl-pyridin-4-yl amino]-Ding-1-alcohol
1H(CDCl 3)d?7.05(m，3H)，6.20(s，1H)，4.8-5.0(m，2H)，3.74(m，1H)，3.66(m，1H)，3.50(m，1H)，2.0-2.29m，9H)，1.55-1.75(m，2H)，0.99(t，3H)ppm.
3-[3-methylol-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl amino]-penta-2-alcohol
1H?NMR(CDCl 3)d?6.86(s，2H)，6.17(s，1H)，4.0(d，1H)，3.9(m，1H)，3.3(m，1H)，2.29(s，3H)，2.14(s，3H)，2.13(s，3H)，2.07(s，6H)，1.8(d，1H)，1.4-1.8(m，2H)，1.25(d，3H)，0.99(t，3H)ppm.
2-[2-(4-chloro-2-methoxyl group-phenoxy group)-3-methylol-6-methyl-pyridin-4-yl amino]-Ding-1-alcohol
1H?NMR(CDCl 3)6.8-7.0(m，3H)，6.2(s，1H)，5.02(d，1H)，4.7(ABq，2H)，3.74(m，5H)，3.350-3.5(m，2H)，2.9(brs，2H)，2.18(s，3H)，1.4-1.7(m，2H)，1.23(m，3H)，0.95(t，3H)ppm.
Embodiment 26
2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methylol-6-methyl-pyridin-4-yl amino]-Ding-1-alcohol
At room temperature, with 4-(S)-(1-methylol-propyl group amino)-6-methyl-2-(4-chloro-2,6-dimethyl-phenoxy group)-nicotinic acid methyl ester and 1M lithium aluminum hydride and the mixture stirring 2hr of aluminum chloride in THF.With mixture cooling with adopt water, 2N NaOH, water quenching and at room temperature stir 10min then.The form white solid also passes through C salt with white solid and filters, and adopts the THF washing.After column chromatography, filtrate is concentrated to drying obtains title compound into white solid.
mp?133-135℃，1H?NMR(CDCl 3)7.00(s，2H)，6.17(s，1H)，5.12(d，1H)，4.90(m，2H)，3.4-3.8(m，3H)，2.12(s，3H)，2.04(s，6H)，1.4-1.6(m，2H)，0.99(t，3H)ppm.
By similar in appearance to the method in aforementioned paragraphs, adopt corresponding methyl esters and lithium aluminum hydride to begin, be prepared as follows compound.
2-{ ethyl-[3-methylol-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amino }-ethanol
1H?NMR(CDCl 3)d?1H?NMR(CDCl 3)6.86(s，2H)，6.53(s，1H)，4.94(s，2H)，3.67(m，2H)，3.1-3.3(m，4H)，2.28(s，3H)，2.20(s，3H)，2.04(s，6H)，1.09(t，3H)ppm.
4-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methylol-6-methyl-pyridin-4-yl amino]-oneself-3-alcohol
mp.145-148℃.1H?NMR(CDCl 3)d?1H?NMR(CDCl 3)7.05(s，2H)，6.16(s，1H)，5.3(d，1H)，4.94(s，2H)，3.67(m，1H)，3.40(m，1H)，2.151(s，3H)，2.09(s，6H)，?1.4-1.8(m，4H)，1.23(m，3H)，1.02(m，6H)ppm.
2-[2-(4-chloro-2-methoxyl group-phenoxy group)-3-methylol-6-methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.8-7.95(m，2H)，5.02(d，1H)，4.74(ABq，2H)，3.74(s，3H)，3.72(m，2H)，3.45m，1H)，2.98(brs，1H)，2.18(s，3H)，1.4-1.7(m，2H)，0.95(t，3H)ppm.
4-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methylol-6-methyl-pyridin-4-yl amino]-oneself-3-alcohol
1H?NMR(CDCl 3)d?7.05(s，2H)，6.16(s，1H)，5.30(d，1H)，4.94(s，2H)，3.67(m，1H)，3.4(m，1H)，2.15(s，3H)，2.09(s，6H)，1.5-1.9(m，4H)，1.01(m，6H)ppm.
[2-(2,4-dimethoxy-phenyl amino)-4-(1-methoxymethyl-propoxy-)-6-methyl-pyridin-3-yl]-methyl alcohol
1H?NMR(CDCl 3)d?6.90(d，1H)，6.42(s，1H)，6.40(d，1H)，5.91(s，1H)，4.42(m，1H)，4.28(s，2H)，3.79(s，3H)，3.76(s，3H)，3.56(m，2H)，3.40(s，3H)，2.33(s，3H)，1.5-1.85(m，2H)，1.02(t.3H)ppm.
Embodiment 27
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6-methyl-nicotinic acid
At room temperature, the mixture stirring of 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester (113mg) and lithium hydroxide Zai diox/THF/ water is spent the night.Mixture is adopted the ammonium chloride quenching and adopts chloroform extraction.The organic layer drying is obtained the title compound that 78mg is a white solid with concentrating.
1H?NMR(CDCl 3)d?10.55(brs，1H)，9.2(d，1H)，7.06(s，2H)，6.3(s，1H)，3.5-3.8(m，3H)，2.11(s，3H)，2.09(s，3H)，2.08(s，3H)，1.78(m，1H)，1.62(m，1H)，1.00(t，3H)ppm.
4-(1-ethyl-Propargyl amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid
mp.131-133℃，1H?NMR(CDCl 3)d?11.29(brs，1H)，9.35(d，1H)，6.91(s，2H)，6.38(s，1H)，4.12(m，1H)，2.88(m，1H)，2.32(s，3H)，2.19(s，3H)，2.09(s，6H)，1.96(m，2H)，1.17(t，6H)ppm.
2-(4-bromo-2,6-dimethyl-phenoxy group)-4-(S)-(1-methoxymethyl-propyl group amino)-6-methyl-nicotinic acid
1H?NMR(CDCl 3)d?10.5(brs，1H)，8.6(d，1H)，7.15(d，2H)，6.25(s，1H)，3.3-3.6(m，3H)，3.38(s，3H)，2.11(s，3H)，2.09(s，3H)，2.08(s，3H)，1.5-1.85(m，2H)，0.91(t，3H)ppm.
4-(2-methoxyl group-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid
1H?NMR(CDCl 3)d?9.44(d，1H)，6.92(s，2H)，6.30(s，1H)，3.80(m，1H)，3.58(m，2H)，3.44(s，6H)，2.33(s，3H)，2.16(s，3H)，2.10(s，6H)ppm.
Embodiment 28
Corresponding by inciting somebody to action [2-(replacement-phenoxy group)-3-chloromethyl-6-methyl-pyridin-4-yl]-(alkyl)-amine and suitable amine reaction, be prepared as follows compound.
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-isobutoxy methyl-6-methyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
1H?NMR(CDCl 3)d?6.94(s，2H)，6.0(s，1H)，5.13(d，1H)，4.7(s，2H)，3.2(m，1H)，3.16(d，2H)，2.02(s，3H)，1.96(s，6H)，1.8(m，1H)，1.3-1.6(m，4H)，0.82(t，6H)，0.8(d，6H)ppm.
[3-ethoxyl methyl-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(1-ethyl-propyl group)-amine
1H?NMR(CDCl 3)d?6.86(s，2H)，6.03(s，1H)，5.30(d，1H)，4.83(s，2H)，3.58(q，2H)，3.35(m，1H)，2.29(s，3H)，2.15(s，3H)，2.06(s，6H)，1.5-1.78(m，4H)，1.23(t，3H)，0.967(t，6H)ppm.
2-[3-butoxymethyl-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?6.85(s，2H)，6.179s，1H)，5.3(d，1H)，4.82(Abq，2H)，3.5-3.8(m，2H)，3.5(t，2H)，2.3(s，3H)，2.15(s，3H，2.02(s，6H)，1.75(brs，1H)，1.5-1.8(m，4H)，1.3-1.5(m，2H)，1.02(t，3H)，0.9(t，3H)ppm.
Embodiment 29
1-[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-ethanol
In THF, under-78 ℃, with 4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-3-carbonyl aldehyde (carbaldehyde) and lithium methide reaction, preparation title compound.After silica gel column chromatography, required product separation is obtained 60.1% water white oil.1H?NMR(CDCl 3)d?6.87(s，2H)，6.06(s，1H)，5.7(q，1H)，3.3(m，1H)，2.29(s，3H)，2.12(s，6H)，2.069s，3H)，1.4-1.7(m，4H)，1.59(d，3H)，0.8-1.0(m，6H)ppm.
Embodiment 30
Acetate 4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl methyl esters
By the acylations of [2-(2,4,6-trimethylammonium-phenoxy group)-3-methylol-6-methyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine, obtain title compound.
1H?NMR(CCl 3)d?6.84(s，2H)，6.04(s，1H)，5.35(s，2H)，5.23(d，1H)，3.32(m，1H)，2.28(s，3H)，2.12(s，3H)，2.08(s，3H)，2.07(s，6H)，1.4-1.7(m，4H)，0.93(t，6H)ppm.
Embodiment 31
2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-(1-hydroxyl-1-methyl-ethyl)-6-methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
At room temperature, in THF, by 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester and excessive 1M Diethylaminoethyl reactive magnesium being spent the night the preparation title compound.After silica gel chromatography, the standard treatment step obtains title compound.
1H?NMR(CDCl 3)d?7.4(brs，1H)，7.01(s，2H)，6.13(s，1H)，3.7(m，1H)，3.6(m，1H)，3.45(m，1H)，2.04(s，3H)，2.03(s，3H)，2.02(s，3H)，1.5-1.7(m，2H)，0.98(t，3H)ppm.
Embodiment 32
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
To [2-(4-chloro-2,6-dimethyl-phenoxy group)-3-chloromethyl-6-methyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine in dry THF (75mg, 0.196mmol) in, be added in the 1.0M BH among the TFH 3(0.59ml, 0.59mmol) and stir 2hr.Mixture is adopted rare HCl quenching and stirs 5min.Reaction mixture is adopted 2N NaOH, water neutralization and adopts ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.Resistates by silica gel chromatography, is obtained the title compound into water white oil.
1H?NMR(CDCl 3)d?7.03(s，2H)，6.08(s，1H)，3.73(d，1H)，3.3(m，1H)，2.15(s，3H)，2.12(s，3H)，2.08(s，6H)，1.4-1.6(m，4H)，0.96(t，6H)ppm.
Embodiment 33
[2-(2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
(43mg, 0.106mmol) solution is added in 1.0M lithium aluminum hydride and the aluminum chloride (28mg) in the ether (0.25ml) to [2-(4-bromo-2-methoxyl group-phenyl amino)-4-(1-ethyl-propyl group amino)-6-methyl-pyridin-3-yl]-methyl alcohol in dry THF.The mixture that obtains at room temperature stirred spend the night.Mixture is adopted water, 2NaOH, water quenching then.Form solid and solid is filtered employing THF, chloroform washing then by C salt.Filtrate is concentrated to drying.Resistates is adopted water and ethyl acetate dilution.Organic layer is separated the dry and concentrated roughage that obtains.After silica gel chromatography, separate title compound.1H?NMR(CDCl 3)d?6.9-7.1(m，3H)，6.07(s，1H)，3.35(d，1H)，3.33(m，1H)，2.14(s，3H)，2.13(s，3H)，2.12(s，6H)，1.5-1.8(m，4H)，0.97(t，6H)ppm.
Embodiment 34
[2-(4-bromo-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
By preparing title compound, be white solid similar in appearance to the method in embodiment 145.
1H?NMR(CDCl 3)d?7.19(s，2H)，6.09(s，1H)，3.36(d，1H)，3.33(m，1H)，2，15(s，3H)，2.12(s，3H)，2.09(s，6H)，1.4-1.8(m，4H)，0.97(t，6H)ppm.
Embodiment 35
4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-phenyl aldehyde
Under-78 ℃, in the solution of [2-(4-bromo-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine in dry THF, add n-Butyl Lithium.After-78 ℃ are down stirred 10min, add N, dinethylformamide also stirs 20min with the mixture that obtains down at-78 ℃, removes the dry ice bath.After stirring 5min, mixture is adopted rare HCl, water quenching and be adjusted to pH7.5 and adopt ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.Resistates is obtained title compound by the silica gel chromatography purifying.1H?NMR(CDCl 3)d?9.93(s，1H)，7.60(s，2H)，6.10(s，1H)，3.75(d，1H)，3.35(m1H)，2.17(s，6H)，2.13(s，3H)，2.12(s，3H)，1.4-1.8(m，4H)，0.97(t，6H)ppm.
Embodiment 36
4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen] and-3,5-dimethyl-phenyl }-methyl alcohol
At room temperature, stir 4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-phenyl aldehyde and the sodium borohydride mixture in methyl alcohol.After standard treatment step and purifying, obtain to be the solid title compound.1HNMR(CDCl 3)d?7.06(s，2H)，6.08(s，1H)，4.64(s，2H)，3.74(d，1H)，3.33(m，1H)，2.14(s，3H)，2.13(s，3H)，2.11(s，6H)ppm.
Embodiment 37
(1-ethyl-propyl group)-[2-(4-methoxymethyl-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine
In the solution of { 4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-phenyl } in dry THF-methyl alcohol, be added in the 60%NaOH in the oil and stir 5min.Add excessive MeI and at room temperature stir 2hr.After standard treatment step and purifying, obtain the title compound of the golden oil of clarification.1HNMR(CDCl 3)d.7.02(s，2H)，6.06(s，1H)，4.40(s，3H)，3.72(d，1H)，3.39(s，3H)，3.36(m，1H)，2.12(s，3H)，2.11(s，3H)，2.10(s，6H)，1.4-1.7(m，4H)，0.95(t，6H)ppm.
Embodiment 38
[2-(4-ethyl-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
Under-78 ℃, in [2-(4-bromo-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine aqueous solution in dry THF, add n-Butyl Lithium.After-78 ℃ are stirred 10min down, add iodoethane and the mixture that obtains is stirred 30min down at-78 ℃, remove the dry ice bath.After stirring 5min, mixture is adopted the salt solution quenching and adopts ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.Resistates is obtained title compound by the silica gel chromatography purifying.
1H?NMR(CDCl 3)d?6.89(s，2H)，6.07(s，1H)，3.72(d，1H)，3.34(m，1H)，2.58(q，2H)，2.16(s，3H)，2.12(s，3H)，2.09(s，6H)，1.4-1.7(m，4H)，1.25(t，3H)，0.96(t，6H)ppm.
Embodiment 39
2-{4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-phenyl }-propan-2-ol
Under-78 ℃, in [2-(4-bromo-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine aqueous solution in dry THF, add n-Butyl Lithium.After-78 ℃ are stirred 10min down, add acetone and the mixture that obtains is stirred 30min down at-78 ℃, remove the dry ice bath.After stirring 5min, mixture is adopted the salt solution quenching and adopts ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.Resistates is obtained title compound by the silica gel chromatography purifying.
1H?NMR(CDCl 3)d?7.17(s，2H)，6.08(s，1H)，3.73(d，1H)，3.33(m，1H)，2.19(s，3H)，2.15(s，3H)，2.12(s，6H)，1.4-1.7(m，4H)，1.26(s，6H)，0.96(t，6H)ppm.
Embodiment 40
1-{4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-phenyl }-ethanol
Under-78 ℃, in [2-(4-bromo-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine aqueous solution in dry THF, add n-Butyl Lithium.After-78 ℃ are stirred 10min down, add acetaldehyde and the mixture that obtains is stirred 30min down at-78 ℃, remove the dry ice bath.After stirring 5min, mixture is adopted the salt solution quenching and adopts ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.Resistates is obtained title compound by the silica gel chromatography purifying.
1H?NMR(CDCl 3)d?7.06(s，2H)，4.84(m，1H)，6.08(s，1H)，3.73(d，1H)，3.35(m，1H)，2.14(s，3H)，2.12(s，3H)，2.11(s，6H)，1.4-1.7(m，4H)，1.51(d，3H)，0.96(t，6H)ppm.
Embodiment 41
(1-ethyl-propyl group)-[2-(4-pseudoallyl-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine
In benzene, under refluxing, by 2-4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen] and-3,5-dimethyl-phenyl }-propan-2-ol and Burgess inner salt (Et 3NS (O) 2NCOOMe) reaction 30 minutes, the preparation title compound.
1H NMR (CDCl 3) d 7.17 (and s, 2H) .6.08 (s, 1H), 5.34 (s, 1H), 5.02 (s, 1H), 3.72 (d, 1H), 3.32 (m, 1H), 2.12 and 2.15 (two the cover s, 12H), 1.4-1.6 (m, 4H), 0.97 (t, 6H) ppm.
Embodiment 42
(1-ethyl-propyl group)-[2-(4-sec.-propyl-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine
Use 10%Pd/C as catalyzer, in ethyl acetate, under 55psi, hydrogenation by (1-ethyl-propyl group)-[2-(4-pseudoallyl-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine, the preparation title compound runs out of up to all starting raw materials.After purifying, obtain the oily title compound.1H?NMR(CDCl 3)d?6.93(s，2H)，6.10(s，1H)，3.73(brs，1H)，3.36(m，1H)，2.18(s，3H)，2.14(s，3H)，2.12(s，6H)，1.4-1.8(m，4H)，1.27(d，6H)，0?98(t，6H)ppm.
Embodiment 43
[3,6-dimethyl-[2-(2,4,6-trimethylammonium-phenoxy group) pyridin-4-yl]-(1-ethyl-allyl group)-amine
Adopt lithium aluminum hydride and aluminum chloride, by the reduction of 4-(1-ethyl-Propargyl amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid, the preparation title compound, it is clarification oily matter.1H?NMR(CDCl 3)d?6.87(s，2H)，6.08(s，1H)，5.7-5.9(m，1H)，5.1-5.3(m，2H)，3.75-4.0(m，2H)，2.30(s，3H)，2.16(s，3H)，2.15(s，3H)，2.08(s，6H)，1.70(m，2H)，1.03(t，3H)ppm.
Embodiment 44
(1-ethyl-propyl group)-[2-(4-fluoro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine
Under-78 ℃, in [2-(4-bromo-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine aqueous solution in dry THF, add n-Butyl Lithium.After-78 ℃ are stirred 10min down, add (PhSO2) 2NF and the mixture that obtains is stirred 30min down at-78 ℃, remove the dry ice bath.After stirring 5min, mixture is adopted the salt solution quenching and adopts ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.Resistates is obtained title compound by the silica gel chromatography purifying.
1H?NMR(CDCl 3)d?6.77(s，1H)，6.73(s，1H)，6.08(s，1H)，3.3(m，1H)，2.12(s，3H)，2.09(s，6H)，2.08(s，3H)，1.4-1.8(m，4H)，0.97(t，6H)ppm.
Embodiment 45
2-[2-(2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl amino]-Ding-1-alcohol
Prepare title compound by method similar in appearance to embodiment 33.
1H?NMR(CDCl 3)d?7.05(m，3H)，6.24(s，1H)，3.4-3.8(m，3H)，2.24(s，3H)，2.16(s，3H)，2.10(s，6H)，1.5-1.8(m，2H)，0.99(t3H)ppm.
Embodiment 46
2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
In the solution of the 2-in dry THF (2,4,6-trimethylammonium-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester, be added in 1.0M lithium aluminum hydride and aluminum chloride in the ether (0.25ml).The mixture that obtains is heated 2hr under refluxing.Mixture is adopted water, 2NaOH, water quenching and stirring then.Form solid and solid is passed through the filtration of C salt, adopt the washing of water and ethyl acetate then.Organic layer is separated, and drying concentrates, and purifying obtains the title compound into white solid.Ultimate analysis C 20H 28N 2O 2. 1/2H 2O calculated value C, 70.90; H, 8.52; N, 8.01; Measured value C, 71.18; H, 8.66; N, 8.30
By similar in appearance to the method in aforementioned paragraphs, use corresponding 2-(phenoxy group of replacement)-4-(alkyl-amino)-6-methyl-nicotinic acid methyl ester and lithium aluminum hydride and aluminum chloride, the compound that is prepared as follows.
3-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl amino]-penta-2-alcohol
1H NMR (CDCl 3) d 6.86 (s, 2H), 6.17﹠amp; 6.13 (two cover s, 1H), 5.0-5.2 (m, 1H), 4.9 (s, 2H), 3.9-4.1 (m, 1H), 3.5 (m, 1H), 3.3 (m, 1H), 2.29 (s, 3H), 2.14 (s, 3H), 2.08 (s, 6H), 1.4-1.8 (m, 2H), 1.27 (m, 3H), 0.98 (m, 3H) ppm.
3-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl amino]-penta-2-alcohol
1H NMR (CDCl 3) d 7.01 (s, 2H), 6.14﹠amp; 6.11 (two sets of s, 1H), 4.04﹠amp; 3.82 (two cover d, 1H), 3.92 (m, 1H), 3.4﹠amp; 3.2 (m, 1H), 2.13 (s, 3H), 2.11 (s, 3H), 2.05 (s, 6H), 1.4-1.8 (m, 2H), 1.25 (two cover d, 3H), 0.98﹠amp; 0.96 (two cover t, 3H) ppm.
Embodiment 47
Benzyl-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-ethyl-amine
Under refluxing, with 4-bromo-3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine (250mg, 0.78mmol), benzyl ethamine (127mg, 0.937mmol), Pd (OAc) 2 (3.6mg, 0.0156mmol), (S)-2,2 '-two (diphenylphosphino)-1,1 '-two naphthalenes (BINAP) (9.7mg, 0.0156mmol), potassium tert.-butoxide (105mg, 0.781mmol) the mixture heating up 2hr in 25ml toluene.Mixture is as cold as room temperature, adopts the water quenching and adopt ethyl acetate extraction.Organic layer is separated dry (Na 2SO 4), filter, concentrate and obtain brown oil.Crude product is obtained title compound by silica gel chromatography.1HNMR(CDCl 3)d?7.2-7.4(m，5H)，6.86(s，2H)，6.41(s，1H)，4.23(s，2H)，3.07(q，2H)，2.31(s，3H)，2.29(s，3H)，2.16(s，3H)，2.06(s，6H)，1.05(t，3H)ppm.
By the method in aforementioned paragraphs, use suitable 4-bromo-2-(phenoxy group of replacement)-3-methyl-6-alkyl or alkoxyl group-pyridine and suitable amine, be prepared as follows compound.
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.06(s，2H)，6.13(s，1H)，4.14(d，1H)，3.3-3.6(m，3H)，3.42(s，3H)，2.16(s，3H)，2.14(s，3H)，2.09(s，6H)，1.5-1.8(m，2H0，1.03(t，3H)ppm.
2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl amino]-3-phenyl-third-1-alcohol
1H?NMR(CDCl 3)d?8.6(d，1H)，7.2-7.4(m5H)，6.84(s，2H)，6.169s，1H)，4.099d，1H)，3.82(m，1H)，3.5-3.7(m，2H)，2.95(d，2H)，2.96(s，3H)，2.27(s，3H)，2.14(s，3H)，2.05(s，6H)ppm.
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.06(s，2H)，6.13(s，1H)，4.2(m，1H)，3.53(m，2H)，3.42(s，3H)，2.19(s，3H)，2.14(s，3H)，2.10(s，6H)，1.5-1.8(m，2H)，1.03(t，3H)ppm.
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethoxyl methyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.06(s，2H)，6.14(s，1H)，4.24(d，1H)，4.4-4.65(m，5H)，2.19(s，3H)，2.14(s，3H)，2.10(s，6H)，1.8(m，1H)，1.65(m，1H)，1.25(t，3H)，1.03(t，3H)ppm.
[3,6-dimethyl-2-(2,4,6-trimethoxy-phenoxy group)-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?6.20(s，2H)，6.08(s，1H)，3.80(s，3H)，3.73(s，6H)，3.8(m，2H)，3.39(m，1H)，3.36(s，3H)，2.23(brs，3H)，2.10(s，3H)，1.74(m，1H)，1.59(m，1H)，0.969t，3H)ppm.
[2-(4-bromo-2,6-dimethyl-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.18(s，2H)，6.09(s，1H)，4.43(d，1H)，3.89(s，3H)，3，25(m，1H)，2.10(s，9H)，1.4-1.8(m，4H)，0.95(t，6H)ppm.
(1-ethyl-propyl group)-[3-methoxyl group-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d6.85(s，2H)，6.07(s，1H)，4.44(m，1H)，3.89(s，3H)，3.23(m，1H)，2.27(s，3H)，2.09(s，6H)，2.08(s，3H)，1.65(m，2H)，1.45(m，2H)，0.93(m，6H)ppm.
[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-3-propyl group-pyridin-4-yl]-(1-ethyl-propyl group)-amine
[2-(4-bromo-2,6-dimethyl-phenoxy group)-6-methyl-3-propyl group-pyridin-4-yl]-(1-ethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.03(s，2H)，6.13(s，1H)，3.8(m，1H)，3.74(s，2H)，3.38(m，1H)，2.15(s，3H)，2.05(s，6H)，1.50-1.7(m，4H)，0.97(t，6H)ppm.
(1-ethyl-propyl group)-[6-methyl-3-propyl group-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amine
[2-(2,4-two chloro-6-methyl-phenoxy groups)-3-methoxyl group-6-methyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
1H?NMR(CDCl 3)7.24(d，1H)，7.1(d，1H)，6.1(s，1H)，4.47(d，1H)，3.9(s，3H)，3.22(m，1H)，2.12(s，3H)，2.08(s，3H)，1.4-1.7(m，4H)，0.9(t，6H)ppm.
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
1H?NMR(CDCl 3)7.02(s，2H)，6.07(s，1H)，4.44(brs，1H)，3.8-3.95(m，3H)，3.23(m，1H)，2.09(s，6H)，2.08(s，3H)，1.4-1.7(m，4H)，0.93(t，6H)ppm.
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.02(s，2H)，6.11(s，1H)，4.71(d，1H)，3.88(s，3H)，3.45(m，2H)，3.37(s，3H)，2.10(s，3H)，2.09(s，6H)，1.73(m，1H)，1.59(m，1H)，0.98(m，3H)ppm.
[2-(2,4-two chloro-6-methyl-phenoxy groups)-3-methoxyl group-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.1-7.25(m，2H)，6.13(s，1H)，4.74(d，1H)，3.91(s，3H)，3.47(m，1H)，3.39(m，2H)，3.37(s，3H)，2.14(s，3H)，2.10(s，3H)，1.78(m，1H)，1.59(m，1H)，0.98(t，3H)ppm.
[2-(4-chloro-2-methoxyl group-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?6.8-7.0(m，3H)，6.17(s，1H)，4.76(d，1H)，3.82(s，3H)，3.75(s，3H)，3.3-3.5(m，3H)，3.35(s，3H)，2.19(s，3H)，1.73(m，1H)，1.56(m，1H)，0.96(t，3H)ppm.
[2-(3-chloro-2,6-dimethoxy-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.12(d，1H)，6.64(d，1H)，6.12(s，1H)＜4.73(d，1H)，3.88(s，3H)，3.78(s，3H)，3.70(s，3H)，3.3-3.5(m，3H)，3.35(s，3H)，2.11(s，3H)，1.5-1.8(m，2H)，0.96(t，3H)ppm.
(1-methoxymethyl-propyl group)-[3-methoxyl group-6-methyl-2-(2,4,6-trimethoxy-phenoxy group)-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?6.19(s，2H)，6.10s，1H)，4.75(m，1H)，3.87(s，3H)，3.80(s，3H)，3.73(s，6H)，3.3-3.5(m，2H)，3.35(s，3H)，2.17(s，3H)，1.78(m，1H)，1.5(m，1H)，0.96(t，3H)ppm.
[3-methoxyl group-2-(4-methoxyl group-2,6-dimethoxy-phenoxy group)-6-methyl-pyridin-4-yl]-(1-ethoxyl methyl-propyl group)-amine
1H?NMR(CDCl 3)d?6.59(s，2H)，6.10(s，1H)，4.70(d，1H)，3.89s，3H)，3.77(s，3H)，3.48(m，1H)，3.39(m，2H)，3.37(s，3H)，2.11(s，3H)，2.10(s，6H)，1.74(m，1H)，1.57(m，1H)，0.98(t，3H)ppm.
[2-(4-chloro-2,6-dimethoxy-phenoxy group)-3-oxyethyl group-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.07(s，2H)，6.16(s，1H)，4.82(d，1H)，4.20(q，2H)，3.54(m，1H)，3.43(m，2H)，3.42(s，3H)，2.15(s，3H)，2.13(s，6H)，1.5-1.9(m，2H)，1.439t，3H)，1.02(t，3H)ppm.
Embodiment 48
2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
At room temperature, in the solution of [1-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-propyl group]-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine in dry THF, be added in 1M tetrabutylammonium among the THF.Mixture is at room temperature stirred 2hr, adopt the water quenching, adopt ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.15% ethyl acetate of use in hexane by the Biotage purifying, obtains the title compound into white solid with resistates as eluent.1HNMR(CDCl 3)d?7.06(s，2H)，6.18(s，1H)，4.04(d，1H)，3.74(m，1H)，3.69(m，1H)，3.53(m，1H)，2.18(s，3H)，2.16(s，3H)，2.10(s，6H)，1.6-1.8(m，2H)，1.04(t，3H)ppm.
By method similar in appearance to aforementioned paragraphs, adopt the corresponding tertiary butyl-dialkyl group-silane oxygen ylmethyl derivative and tetrabutylammonium, be prepared as follows compound.
2-[3-methoxyl group-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?6.85(s，2H)，6.15(s，1H)，4.57(d，1H)，3.91(s，3H)，3.72(m，1H)，3.61(m，1H)，3.41(m，1H)，2.27(s，3H)，2.10(s，3H)，2.07(s，6H)，1.5-1.8(m，3H)，0.98(t，3H)ppm.
2-[2-(4-chloro-2,6-dimethoxy-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.02(s，2H)，6.16(s，1H)，4.60(d，1H)，3.91(s，3H)，3.71(m，1H)，3.61(m，1H)，3.40(m，1H)，2.10(s，3H)，2.08(s，6H)，1.8(brs，1H)，1.71(m，1H)，1.68(m，1H)，0.99(t，3H)ppm.
4-[4-(1-methylol-propyl group amino)-3-methoxyl group-6-methyl-pyridine-2-base oxygen]-3,5-dimethyl-benzonitrile
1H?NMR(CDCl 3)d?7.35(s，2H)，6.19(s，1H)，4.7(brs，1H)，3.88(s，3H)，3.731(m，1H)，3.64(m，1H)，3.43(m，1H)，2.14(m，9H)，1.8(brs，1H)，1.71(m，1H)，1.58(m，1H)，0.99(t，3H)ppm.
Embodiment 49
Prepare title compound in the following way: at room temperature, by 2-[2-(4-chloro-2,6-dimethoxy-phenoxy group)-3,6-dimethyl-pyridine-4-(S)-Ji amino]-the Dess Martin oxidation of Ding-1-alcohol methylene dichloride, subsequently by in THF, using methylmagnesium-bromide to carry out grignard reaction.1HNMR(CDCl 3)d?7.07(s，2H)，6.18(s，1H)，4.3(brs，1H)，3.32(m，1H)，2.22(s，3H)，2.17(s，3H)，2.11(s，6H)，1.6-1.8(m，2H)，1.30(d，3H)，1.01(t，3H)ppm.
Embodiment 50
2-[2-methyl-6-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl amino]-Ding-1-alcohol
Under 160 ℃, run out of the preparation title compound up to all starting raw materials by heating 2-(2,4,6-trimethylammonium-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6-methyl-nicotinic acid.Ultimate analysis C 19OH 26N 2O 2H 2O calculated value C, 68.65; H, 8.49; N, 8.42; Measured value C, 69.04; H, 8.14; N, 8.91
Embodiment 51
(1-ethyl-Propargyl)-[2-methyl-6-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amine]
Prepare title compound by method similar in appearance to embodiment 163.
1H?NMR(CDCl 3)d?6.89(s，2H)，6.12(d，1H)，5.41(d，1H)，3.9-4.2(m，2H)，2.37s，3H)，2.30(s，3H)，2.27(m，1H)，1.76(m，2H)，1.05(t，3H)ppm.
Embodiment 52
2-(4-bromo-2,6-dimethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-pyridine-3-alcohol
Under 0 ℃, in [2-(4-bromo-2,6-dimethoxy-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-solution of (1-ethyl-propyl group)-amine in methylene dichloride, add BBr 3And stirring hr.Mixture is adopted the water quenching and adopts chloroform extraction.Organic layer is separated drying and the concentrated title compound that obtains.1H?NMR(CDCl 3)d?7.20(s，2H)，6.12(s，1H)，4.77(d，1H)，3.27(m，1H)，2.13(s，3H)，2.10(s，6H)，1.4-1.8(m
By similar in appearance to the method in aforementioned paragraphs, adopt suitable [2-(substituent phenoxy)-3-methoxyl group-6-methyl-pyridin-4-yl]-(alkyl)-amine and BBr 3Or BCl 3Beginning is prepared as follows compound.
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-3-alcohol
1H?NMR(CDCl 3)d6.85(s，2H)，6.10(s，1H)，5.12(brs，1H)，4.21(m，1H)，3.27(m，1H)，2.28(s，3H)，2.09(s，9H)，1.5-1.8(m，4H)，0.96(m，6H)ppm.
4-(S)-(1-methylol-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-3-alcohol
1H?NMR(CDCl 3)d?6.85(s，2H)，6.17(s，1H)，5.13(brs，1H)，4.28(d，1H)，3.73(m，1H)，3.60(m，1H)，3.50(m，1H)，2.27(s，3H)，2.12(s，3H)，2.07(s，6H)，1.75(brs，1H)，1.5-1.7(m，2H)，0.99(t，3H)ppm.
2-(4-chloro-2,6-dimethoxy-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-pyridine-3-alcohol
1H?NMR(CDCl 3)d?7.032(s，2H)，6.10(s，1H)，5.2(brs，1H)，4.35(brs，1H)，3.71(m，1H)，3.61(m，1H)，3.40(m，1H)，2.07(s，9H)，1.8(brs，1H)，1.71(m，1H)，1.60(m，1H)，0.99(m，3H)ppm.
2-(4-chloro-2,6-dimethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-pyridine-3-alcohol
1H?NMR(CDCl 3)d?7.02(s，2H)，6.10(s，1H)，5.02(brs，1H)，4.22(brs，1H)，3.25(brs，1H)，2.08(brs，9H)，1.62(m，2H)，1.52(m，2H)，0.95(brs，6H)ppm.
Embodiment 53
Mono Chloro Acetic Acid 4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl ester
At 0 ℃ under room temperature, in THF, by making the reaction of 4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pure and mild chloroacetyl chloride of pyridine-3-/triethylamine, the preparation title compound.
to?rt.1H?NMR(CDCl 3)d?6.84(s，2H)，6.15(s，1H)，4.3(s，2H)，4.0(d，1H)，3.3(m，1H)，2.28(s，3H)，2.17(s，3H)，2.08(s，6H)，1/6-1.7(m，4H)，0.9(t，6H)ppm.
Embodiment 54
2-(4-chloro-2,6-dimethoxy-phenoxy group)-4-[(1-ethyl-propyl group amino)-methyl-amino]-6-methyl-pyridine-3-alcohol
1H?NMR(CDCl 3)d?7.03(s，2H)，6.25(s，1H)，5.4(brs，1H)，3.93(m，1H)，2.70(s，3H)，2.12(s，3H)，2.08(s，6H)，1.55(m，4H)，0.89(t，6H)ppm.
Embodiment 55
[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-acetonitrile
1H?NMR(CDCl 3)d?6.87(s，2H)，6.13(s，1H)，3.83(d，1H)，3.79(s，2H)，3.38(m，1H)，2.30(s，3H)，2.27(s，3H)，2.21(s，6H)，1.4-1.8(m，4H)，1.00(t，6H)ppm.
Embodiment 56
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-3-carbonyl aldehyde
1H?NMR(CDCl 3)d?10.52(s，1H)，9.26(d，1H)，6.89(s，2H)，6.11(s，1H)，3.42(m，1H)，2.31(s，3H0，2.15(s，3H)，2.11(s，6H)，1.45-1.75(m，4H)，0.97(t，6H)ppm.
Embodiment 57
(1-ethyl-propyl group)-[3-[(1-ethyl-propyl group imino-)-methyl]-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?10.33(d，1H)，8.94(s，1H)，6.89(s，2H)，6.10(s，1H)，3.41(m，1H)，2.86(m，1H)，2.99(s，3H)，2.14(s，3H)，2.10(s，6H)，1.4-1.89m，8H)，0.94(t，6H)，0.87(t，6H)ppm.
Embodiment 58
2-[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl methyl]-dimethyl malonate
At room temperature, within 1hr, to dimethyl malonate (60mg, 0.44mmol) and in oil 60%NaH (20mg, 0.44mmol) in the solution in dry THF, add [3-chloromethyl-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(1-ethyl-propyl group)-amine hydrochlorate (50mg, 0.146mmol).Mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.Resistates is obtained title compound into clarified oil by silica gel chromatography.1HNMR(CDCl 3)d?6.88(s，2H)，6.03(s，1H)，4.85(m，1H)，4.03(t，1H)，3.73(s，6H)，3.26(m，1H)，3.18(d，2H)，2.30(s，3H)，2.13s，3H)，2.07(s，6H)，1.5-1.8(m，4H)，0.97(t，6H)ppm.
Embodiment 59
2-[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl methyl]-propanedioic acid two and propyl ester
Prepare title compound by method similar in appearance to embodiment 581.1H NMR (CDCl 3) d 6.87 (s, 2H), 6.03 (s, 1H), 5.10 (m, 2H), 4.90 (d, 1H), 3.94 (t, 1H), 3.31 (m, 1H), 3.16 (d, 2H), 2.30 (s, 3H), 2.13s, 3H0,2.08 (s, 6H), 1.5-1.8 (m, 4H), 1.1-1.3 (two cover d, 6H), 0.97 (t, 6H) ppm.
Embodiment 60
4-(1-ethyl-propoxy-)-6-methyl-3-nitro-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
To 2-chloro-4-(1-ethyl-propoxy-)-6-methyl-3-nitro-pyridine (500mg, 1.93mmol) and 2 (289mg 2.13mmol) adds potassium tert.-butoxide in the mixture in dry THF.The mixture that obtains at room temperature stirred spend the night.Mixture is adopted water, salt solution quenching and employing ethyl acetate extraction 3 times.Organic layer is separated dry (MgSO 4) be concentrated to drying.After silica gel chromatography, obtain title compound with light yellow crystal.Mp 106-109 ℃. ultimate analysis C 20H 26N 2O 4Calculated value C, 67.02; H, 7.31; N, 7.82; Measured value, C, 67.34; H, 7.40; N, 7.42.
Embodiment 61
4-(1-ethyl-propoxy-)-6-methyl-3-nitro-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl amine
Under 50psi, with 4-(1-ethyl-propoxy-)-6-methyl-3-nitro-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine (150mg, 0.418mmol) and the mixture hydrogenation of 10%Pd/C (23mg) in ethanol 15 hours.Add other 10Pd/C and with the other 24hr of mixture hydrogenation that obtains.Mixture is concentrated to drying by the filtration of C salt with filtrate, obtains the 200mg roughage.After column chromatography, obtain the corresponding HCl salt of title compound, be white solid, mp 96-98 ℃.
Embodiment 62
[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-dimethylamine
Under-78 ℃, in the solution of the 4-in dry THF (1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl amine, add two (trimethyl silyl) acid amides lithiums.After-78 ℃ are stirred 10 minutes down, add excess iodine methane.After adopting the water quenching and adopting ethyl acetate extraction, separate title compound.By the silica gel chromatography roughage, obtain being the foamed title compound of brown.
Embodiment 63
N-[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-succinamic acid
At room temperature, with 4-(1-ethyl-propoxy-)-6-methyl-3-nitro-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl amine (100mg, 0.304mmol), succinyl oxide (31mg, 0.304mmol) spend the night with triethylamine by the mixture stirring in methylene dichloride.Mixture is adopted the water quenching, and adopt dichloromethane extraction.Organic layer is separated the dry and concentrated solid that obtains.After silica gel column chromatography, separate title compound, it is a white crystal.
1H?NMR(CDCl 3)d?6.90(brs，1H)，6.84(s，2H)，6.37(s，1H)，4.2(m，1H)，2.6-2.8(m，4H)，2.28(s，3H)，2.22(s，3H)，2.03(s，6H)，1.69(m，4H)，0.94(t，6H)ppm.
Embodiment 64
4-(1-ethyl-propoxy-)-3,6-dimethyl-2-[3-(2,4,6-trimethylammonium-pyridyloxy)]-pyridine
In the solution of 3-amylalcohol (0.11ml) in dry THF, add sodium hydride (in oil 60%, 20mg).After stirring 5min, be added in the 4-chloro-2 among the THF, 5-dimethyl-6-[3-(2,4,6-trimethylammonium-pyridyloxy)]-pyridine (92mg, solution 0.332mmol).Add DMSO and with the mixture heated overnight under 130 ℃ of oil baths that obtains.Mixture is adopted water, salt solution quenching and adopts ethyl acetate extraction 3 times.Organic layer is separated dry (MgSO 4) be concentrated to drying.After silica gel chromatography, obtain title compound with clarified oil.
1H?NMR(CDCl 3)d?6.88(s，1H)，6.37(s，1H)，4.21(m，1H)，2.5(s，3H)，2.29(s，3H)，2.19(s，3H)，2.18(s，3H)，2.07(s，3H)，1.70(m，4H)，0.98(t，6H)ppm.
Oil is prepared as corresponding HCl salt obtains white solid (63mg).
By similar in appearance to method at embodiment 64, adopt suitable 6-alkyl-4-chloro-or bromo-3-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine and 3-amylalcohol/NaH to begin, be prepared as follows the title compound of embodiment 65 and 66:
Embodiment 65
6-ethyl-4-(1-ethyl-propoxy-)-3-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
1H?NMR(CDCl 3)d?6.87(s，2H)，6.28(s，1H)，4.20(m，1H)，2.46(q，2H)，2.30(s，3H)，2.20(s，3H)，2.07(s，6H)，1.72(m，4H)，1.05(t，3H)，0.99(t，6H)ppm.
Embodiment 66
4-(1-ethyl-propoxy-)-2-(4-fluoro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridine
Water white oil.Ultimate analysis C 20H 26FNO 2Calculated value C, 72.48; H, 7.91; N, 4.23; Measured value C, 72.39; H, 7.77; N, 4.10.
Embodiment 67
[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-yl]-(2,4,6-trimethylammonium-phenyl)-amine
To (240mg in solution 0.673mmol), adds lithium aluminum hydride and aluminum chloride at the 4-of dry THF (1-ethyl-propoxy-)-6-methyl-(2,4,6-trimethylammonium-phenyl amino)-nicotinic acid.The mixture that obtains was heated 3 hours under refluxing.Mixture is adopted 0.1ml water and 0.1ml2N NaOH quenching, adopt water and ethyl acetate quenching then, separate organic layer, drying, concentrate, obtain the 250mg brown oil.After silica gel column chromatography, obtain 170mg (78%) title compound, it is prepared as HCl salt obtains title compound, be white solid.mp.132-133℃.1H?NMR(CDCl 3)d?6.87(s，2H)，6.09(s，1H)，5.399brs，1H)，4.13(m，1H)，2.27(s，3H)，2.22(s，3H)，2.15(s，6H)，1.98(s，3H)，1.67(m，4H)，0.94(t，6H)ppm.
Embodiment 68
[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-methyl alcohol
To (100mg in solution 0.281mmol), adds BH at the 4-of dry THF (1-ethyl-propoxy-)-6-methyl-(2,4,6-trimethylammonium-phenyl amino)-nicotinic acid 3.DMS.With the mixture heated overnight under refluxing that obtains.Mixture is adopted rare HCl quenching and stirred 30 minutes, regulate pH, adopt ethyl acetate extraction then to 7.5-8.5.Organic layer is separated the dry and concentrated 100mg brown oil that obtains.After silica gel column chromatography, obtain 91mg (95%) title compound, be the white foam shape.Ultimate analysis C 21H 30N 2O 2.1/2H 2O calculated value C, 71.76; H, 8.89; N, 7.97; Measured value C, 71.97; H, 8.90; N, 7.69.
Embodiment 69
[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-oxo-acetonitrile
Prepare title compound in the following way: in benzene, make the reaction of [4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-methyl alcohol and thionyl chloride, be concentrated to drying, react with the cyaniding diethyl aluminum subsequently.After standard treatment step and silica gel column chromatography, obtain title compound, mp.108-110 ℃ into yellow crystals.
1H?NMR(CDCl 3)d?8.57(s，1H)，6.97(s，2H)，6.37(s，1H)，4.46(m，1H)，2.35(s，3H)，2.34(s，3H)，2.09(s，6H)，1.6-1.8(m，4H)，0.99(t，6H)ppm.
Embodiment 70
[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-imidazoles-1-base-ketone (methanone)
To the 4-in 2ml DMF (1-ethyl-propoxy-)-6-methyl-(2,4,6-trimethylammonium-phenyl amino)-(250mg is in solution 0.701mmol) for nicotinic acid, (190mg at room temperature stirs 1.19mmol) and with the mixture that obtains and to spend the night to add carbonyl dimidazoles.After standard treatment step and silica gel column chromatography, obtain to be mp.120-122 ℃ of golden crystalline 260mg (91.2%) title compound, ultimate analysis C 24H 30N 4O 2.1/4H 2O calculated value: C, 70.13; H, 7.48; N, 13.63; Measured value: C, 70.06; H, 7.69; N, 13.37.
Embodiment 71
2-[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-propan-2-ol
By in THF, at room temperature make [4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-imidazoles-1-base-ketone and excessive MeMgBr reaction, obtain title compound.After standard treatment step and silica gel column chromatography, obtain title compound into brown solid.Mp.81-83 ℃, ultimate analysis C 22H 30N 2O 2.1.5H 2O calculated value: C, 69.49; H, 9.38; N, 7.04; Measured value: C, 69.49; H, 9.27; N, 6.86
Embodiment 72
2-[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl methyl]-dimethyl malonate
Prepare title compound in the following way: in benzene, make [4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-methyl alcohol and thionyl chloride reaction, be concentrated to drying, in DMSO, react subsequently with propanedioic acid methyl esters/NaH.After standard treatment step and silica gel column chromatography, obtain to be mp.96-98 ℃ of solid title compound; Ultimate analysis C 26H 36N 2O 5.1/3H 2O calculated value: C, 67.51; H, 7.99; N, 6.04; Measured value: C, 67.48; H, 7.99; N, 6.02.
Embodiment 73
3-[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-propionic acid
Under refluxing, carry out 2-[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl methyl of phosphoric acid/water]-hydrolysis of dimethyl malonate, obtain title compound into white foam.Ultimate analysis C 23H 32N 2O 3.3/4H 2O calculated value: C, 69.40; H, 8.48; N, 7.04; Measured value: C, 69.17; H, 8.62; N, 6.90.
Embodiment 74
[3-amino methyl-4-(1-ethyl-propoxy-)-6-methyl-pyridine-2-yl]-(2,4,6-trimethylammonium-phenyl)-amine
Prepare title compound in the following way: in benzene,, be concentrated to drying with the reaction of [4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-methyl alcohol and thionyl chloride, subsequently at room temperature with NH 3(g) reaction.After standard treatment step and silica gel column chromatography, obtain title compound, ultimate analysis C into golden oil (80%) 21H 31N 3O. calculated value: C, 73.86; H, 9.15; N, 12.3; Measured value: C, 73.50; H, 9.25; N, 11.39.
Embodiment 75
2-chloro-N-[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl methyl]-ethanamide
By adopting chloroacetyl chloride to carry out 3-amino methyl-4-(1-ethyl-propoxy-)-6-methyl-pyridine-2-yl]-acylations of (2,4,6-trimethylammonium-phenyl)-amine, the preparation title compound.After standard treatment step and silica gel column chromatography, obtain to be greyish white crystalline title compound, mp.142-144 ℃, ultimate analysis C 23H 32ClN 3O 2. calculated value: C, 66.09; H, 7.72; N, 10.05; Measured value: C, 65.81; H, 7.64; N, 9.86.
Embodiment 76
[3-dimethylaminomethyl-4-(1-ethyl-propoxy-)-6-methyl-pyridine-2-yl]-(2,4,6-trimethylammonium-phenyl)-amine hydrochlorate
Prepare title compound in the following way: in benzene,, be concentrated to drying, at room temperature react subsequently with dimethylamine with [4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-methyl alcohol and thionyl chloride reaction.After standard treatment step and silica gel column chromatography, obtain title compound into oil.Preparing corresponding HCl salt is white solid, mp.85-88 ℃, and ultimate analysis C 23H 35N 3O.2HCl.1.5H 2O calculated value: C, 58.83; H, 8.588; N, 8.94; Measured value: C, 58.32; H, 8.5327; N, 8.64.
Embodiment 77
Dithiocarbonic acid O-ethyl ester S-[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl methyl]-ester
Prepare title compound in the following way: in benzene,, be concentrated to drying, at room temperature react subsequently with NaSCSOEt with [4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-methyl alcohol and thionyl chloride reaction.After standard treatment step and silica gel column chromatography, obtain title compound into white solid.Mp.55-57 ℃, ultimate analysis C 24H 34N 2O 2S 2. calculated value: C, 64.54; H, 7.67; N, 6.27; Measured value: C, 64.67; H, 7.78; N, 6.26.
Embodiment 78
4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-niacinamide
Prepare title compound in the following way: in benzene,, be concentrated to drying with the reaction of 4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-nicotinic acid and thionyl chloride, subsequently at room temperature with NH 3(g) reaction.After standard treatment step and silica gel column chromatography, obtain title compound into oil.Preparing corresponding HCl salt is pale solid, mp.185-187 ℃; Ultimate analysis C 21H 29N 3O 2. calculated value: C, 70.96; H, 8.22; N, 11.82; Measured value: C, 71.30; H, 8.33; N, 11.78.
Embodiment 79
4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-cigarette nitrile
In THF, by making 4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-niacinamide and triphosgene/triethylamine reaction, preparation title compound, mp105-107 ℃.1HNMR(CDCl 3)d6.90(s，2H)，6.26(brs，1H)，6.05(s，1H)，4.24(m，1H)，2.28(s，3H)，2.25(s，3H)，2.17(s，6H)，1.72(m，H)，0.97(t，6H)ppm.
Embodiment 80
4-(1-ethyl-propoxy-)-6, N, N-trimethylammonium-2-(2,4,6-trimethylammonium-phenyl amino)-niacinamide
Prepare title compound in the following way: in benzene,, be concentrated to drying, at room temperature react subsequently with dimethylamine with 4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino) nicotinic acid and thionyl chloride reaction.After standard treatment step and silica gel column chromatography, obtain title compound into oil.Preparing corresponding HCl salt is white solid.Mp.197-200 ℃, ultimate analysis C 23H 33N 3O 2.H 2O. calculated value: C, 63.07; H, 8.28; N, 9.59; Measured value: C, 63.24; H, 8.07; N, 9.61.
Embodiment 81
[4-(1-ethyl-propoxy-)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-acetonitrile
Prepare title compound in the following way: will [4-(1-ethyl-propoxy-)-6-methyl-2-(2 in benzene, 4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-methyl alcohol and thionyl chloride reaction, be concentrated to drying, in DMSO, at room temperature react subsequently with potassium cyanide.After standard treatment step and silica gel column chromatography, obtain to be greenish orange look solid title compound.mp.112-115℃。1H?NMR(CDCl 3)d?6.9(s，2H)，6.14(s，1H)，5.6(brs，1H)，4.22(m，1H)，3.49(s，2H)，2.28(s，3H)，2.22(s，3H)，2.16(s，6H)，1.71(m，4H)，0.95(t，6H)ppm.
Embodiment 82
[2-(4-bromo-2,6-dimethyl-phenyl amino)-4-(1-ethyl-propoxy-)-6-methyl--pyridin-3-yl]-methyl alcohol
(130mg in solution 0.309mmol), adds BH to the 4-in dry THF (1-ethyl-propoxy-)-6-methyl-2-(4-bromo-2,6-dimethyl-phenyl amino)-nicotinic acid 3.DMS.With the mixture heated overnight under refluxing that obtains.Mixture is adopted rare HCl quenching and stirred 30 minutes, regulate pH, adopt ethyl acetate extraction then to 7.5-8.5.Organic layer is separated the dry and concentrated 100mg brown oil that obtains.After silica gel column chromatography, obtain 110mg (87.3%) title compound, be the white semisolid.
1H?NMR(CDCl 3)d?7.25(s，2H)，6.85(brs，1H)，4.8(brs，2H)，4.18(m，1H)，2.2(s，3H)，2.07(s，6H)，1.7(m，4H)，0.95(t，6H)ppm.
Embodiment 83
[2-(4-chloro-2,6-dimethyl-phenyl amino)-4-(1-ethyl-propoxy-)-6-methyl--pyridin-3-yl]-methyl alcohol
In the solution of the 4-in dry THF (1-ethyl-propoxy-)-6-methyl-2-(4-chloro-2,6-dimethyl-phenyl amino)-nicotinic acid, add BH 3.DMS.With the mixture heated overnight under refluxing that obtains.Mixture is adopted rare HCl quenching and stirred 30 minutes, regulate pH, adopt ethyl acetate extraction then to 7.5-8.5.Organic layer is separated the dry and concentrated brown oil that obtains.After silica gel column chromatography, obtain title compound, be green oil.
1H?NMR(CDCl 3)d?7.02(s，2H)，6.83(brs，1H)，4.78(s，2H)，4.14(m，1H)，2.2(s，3H)，2.13(s，6H)，1.66(m，4H)，0.93(9t，6H)ppm.
Embodiment 84
[2-(2,4-two chloro-phenyl aminos)-4-(1-ethyl-propoxy-)-6-methyl-pyridin-3-yl]-methyl alcohol
In the solution of the 4-in dry THF (1-ethyl-propoxy-)-6-methyl-2-(2,4-two chloro-phenyl aminos)-nicotinic acid, add BH 3.DMS.With the mixture heated overnight under refluxing that obtains.Mixture is adopted rare HCl quenching and stirred 30 minutes, regulate pH, adopt ethyl acetate extraction then to 7.5-8.5.Organic layer is separated the dry and concentrated gold oil that obtains.After silica gel column chromatography, obtain title compound, be golden oil.
1H?NMR(CDCl 3)d?8.44(d，1H)，8.18(s，1H)，7.32(d，1H)，7.179d，1H)，6.28(s，1H)，4.82(s，2H)，4.21(m，1H)，2.42(s，3H)，1.6-1.8(m，4H)，0.94(t，6H)ppm.
Embodiment 85
[2-(2,4-dimethoxy-phenyl amino)-4-(1-methoxymethyl-propoxy-)-6-methyl-pyridin-3-yl]-methyl alcohol
Method by in embodiment 84 adopts corresponding nicotinic acid and BH 3.DMS begin the preparation title compound.1H?NMR(CDCl 3)d6.91(d，1H)，6.50(m，2H)，5.91(s，1H)，4.42(m，1H)，4.281(s，2H)，3.79(s，3H)，3.76(s，3H)，3.56(m，2H)，3.40(s，3H)，2.33(s，3H)，1.6-1.8(m，2H)，1.02(t，3H)ppm.
Embodiment 86
[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-imidazoles-1-base-ketone
By the method in embodiment 70, adopt corresponding nicotinic acid and carbonyl dimidazoles to begin, the preparation title compound.
1HNMR(CDCl 3)d?8.1(s，1H)，7.52(s，1H)，7.05(s，1H)，6.78(s，2H)，6.17(s，1H)，5.97(d，1H)，3.3(m，1H)，2.23(s，3H)，2.18(s，3H)，2.00(s，6H)，1.4-1.7(m，4H)，0.93(t，6H)ppm.
Embodiment 87
1-[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-ethyl ketone
In methylene dichloride, by making [4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl]-imidazoles-1-base-ketone and methylmagnesium-bromide/ether reaction, preparation title compound.1H?NMR(CDCl 3)d?9.7(d，1H)，6.88(s，2H)，6.10(s，1H)，3.32(m，1H)，2.73(s，3H)，2.31(s，3H)，2.10(s，3H)，2.09(s，6H)，1.5-1.7(m，4H)，0.95(t，6H)ppm.
Embodiment 88
(1-ethyl-propyl group)-[6-methyl-3-propyl group-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?6.84(s，2H)，6.04(s，1H)，3.81(d，1H)，3.31(m，1H)，2.56(t，2H)，2.27(s，3H)，2.12(s，3H)，2.04(s，6H)，1.4-1.7(6H)，1.02(t，3H)，0.93(t，6H)ppm.
Embodiment 89
2-[4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl methyl]-dimethyl malonate
By the method in embodiment 72, the preparation title compound.
1H?NMR(CDCl 3)6.87(s，2H)，6.01(s，1H)，5.05(m，1H)，3.70(s，6H)，3.4(s，2H)，3.3(m，1H)，2.27(s，3H)，2.12(s，3H)，2.07(s，6H)，1.4-1.7(m，4H)，1.48(s，3H)，0.949t，6H)ppm.
Embodiment 90
[4-(1-ethyl-propoxy-)-6-methyl-pyridine-2-yl]-(2,4,6-trimethylammonium-phenyl)-amine
In 160 ℃ of oil baths, by the decarboxylation of corresponding nicotinic acid, the preparation title compound.Mp.98-100 ℃; Ultimate analysis C 20H 28N 2O calculated value C, 76.88; H, 9.03; N, 8.97; Measured value: C, 76.97; H, 9.21; N, 8.99.
By 3-methoxyl group-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-4-carbonyl aldehyde and the reaction of bromination alkyl magnesium in THF, prepare the following compound of embodiment 204 and 205:
Embodiment 91
2-ethyl-1-[3-methoxyl group-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-Ding-1-alcohol
1H?NMR(CDCl 3)6.87(s，2H)，6.72(s，1H)，4.90(t，1H)，4.00(s，3H)，2.29(s，3H)，2.19(s，3H)，2.06(s，6H)，1.2-1.6(m，5H)，0.92(t，3H)，0.88(t，3H)ppm.
Embodiment 92
1-[3-methoxyl group-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-2-methyl-Ding-1-alcohol
1H?NMR(CDCl 3)6.88(s，2H)，6.74(s，1H)，5.00(m，1H)，4.00(s，3H)，2.29(s，3H)，2.19(s，3H)，2.06(s，6H)，1.4-1.9(m，3H)，0.992(t，3H)，0.989(d，3H)ppm.
Embodiment 93
1-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-third-1-alcohol
To-78 ℃ of 4-bromo-3 in dry THF, in the solution of 6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine, adding nBuLi also stirred 20 minutes under this temperature.Add excessive propionic aldehyde and descend stirring 2 hours at-78 ℃.Mixture is adopted the water quenching, adopt ethyl acetate extraction.Organic layer is adopted the salt water washing, dry and concentrated.After column chromatography, obtain pale solid.mp.119-120℃。
1H?NMR(CDCl 3)d?6.86(s，3H)，4.90(m，1H)，2.281(s，3H)，2.28(s，3H)，2.21(s，3H)，2.02(s，6H)，1.65-1.8(m，2H)，1.00(t，3H)ppm.
Embodiment 94
4-(1-methoxyl group-propyl group)-3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
Prepare title compound: 1-[3 in the following way, 6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-reaction of the pure and mild sodium hydride of third-1-, adopt the methyl iodide quenching subsequently.
1H?NMR(CDCl 3)d?6.87(s，2H)，6.74(s，1H)，4.33(m，1H)，3.25(s，3H)，2.28(s，3H)，2.27(s，3H)，2.21(s，3H)，2.03(s，6H)，1.6-1.8(m，2H)，0.94(t，3H)ppm.
Embodiment 95
4-(1-oxyethyl group-propyl group)-3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
Prepare title compound in the following way: make 1-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-the pure and mild sodium hydride reaction of third-1-, adopt the iodoethane quenching subsequently.
1H?NMR(CDCl 3)d?6.86(s，2H)，6.77(s，1H)，4.41(m，1H)，3.22-3?45(m，2H)，2.28(s，3H)，2.27(s，3H)，2.21(s，3H)，2.03(s，6H)，1.6-1.8(m，2H)，1.20(t，3H)，0.95(t，3H)ppm.
Embodiment 96
4-(1-allyloxy-propyl group)-3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
Prepare title compound in the following way: make 1-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-the pure and mild sodium hydride reaction of third-1-, adopt the allyl bromide 98 quenching subsequently.
1H?NMR(CDCl 3)d?6.87(s，2H)，6.78(s，1H)，5.93(m，1H)，5.1-5.3(m，2H)，4.48(m，1H)，3.95(m，1H)，3.76(m，1H)，2.29(s，3H)，2.26(s，3H)，2.21(s，3H)，2.03(s，6H)，1.6-1.8(m，2H)，0.96(t，3H)ppm.
Embodiment 97
4-(1-butoxy-propyl group)-3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
Prepare title compound in the following way: make 1-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-the pure and mild sodium hydride reaction of third-1-, adopt the butyl iodide quenching subsequently.
1H?NMR(CDCl 3)d?6.86(s，2H)，6.76(s，1H)，4.37(m，1H)，3.35(m，1H)，3.25(m，1H)，2.28(s，3H)，2.26(s，3H)，2.20(s，3H)，2.03(s，6H)，1.6-1.8(m，2H)，1.5-1.65(m，2H)，1.3-1.5(m，2H)，0.96(t，3H)，0.89(t，3H)ppm.
By the method in embodiment 93, adopt suitable 4-bromo-2-(substituent phenoxy)-pyridine derivate and nBuLi reaction, adopt suitable aldehyde quenching subsequently, be prepared as follows the title compound of embodiment 98-102.
Embodiment 98
1-[2-(2,4-two chloro-6-methyl-phenoxy groups)-3-methoxyl group-6-methyl-pyridin-4-yl]-2-ethyl-Ding-1-alcohol
A raceme 1H NMR (CDCl 3) d 7.28 (d, 1H), 7.14 (d4.00 (s, 3H), 2.21 (s, 3H), 2.13 (s, 3H), 1.3-1.65 (m, 5H), 0.93 (t, 3H), 0.87 (t, 3H) ppm.
Another raceme 1H NMR (CDCl 3) d 7.18 (s, 1H), 7.08 (d, 1H), 6.74 (d, 1H), 5.17 (m, 1H), 3.93 (s, 3H), 2.75 (m, 1H), 2.1-2.25 (m, 1H), 2.16 (s, 3H), 2.13 (s, 3H), 1.6-1.8 (m, 2H), 1.0-1.3 (m, 2H), 0.93 (t, 3H), 0.72 (t, 3H) ppm.
Embodiment 99
1-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-2,2,2-three fluoro-ethanol
Mp.134-139 ℃, ultimate analysis C 18H 20F 3NO 2Calculated value: C, 63.71; H, 5.94; N, 4.13; Measured value: C, 63.59; H, 6.00; N, 4.02.
Embodiment 100
1-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-2,2,2-three fluoro-ethanol
1H?NMR(CDCl 3)d?6.979s，2H)，6.19(s，1H)，2.14(s，6H)，2.06(s，6H)ppm.
Embodiment 101
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-pyridine-2-base-methyl alcohol
1H?NMR(CDCl 3)d?8.61(d，1H)，7.71(m，1H)，7.30(m，1H)，7.10(m，1H)，7.03(s，2H)，6.70(s，1H)，6.03(s，1H)，2.37(s，3H)，2.16(s，3H)，2.03(s，6H)，ppm.
Embodiment 102
1-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-2-ethyl-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.05(s，2H)，6.759s，1H)，4.90(t，1H)，3.98(s，3H)，2.19(s，3H)，2.06(s，6H)，2.13(d，1H)，1.25-1.65(m，5H)，0.92(t，3H)，0.87(t，3H)ppm.
By in the DMSO/ methylene dichloride, adopting Dess Martin reagent or in methylene dichloride, adopting pyridinium chlorochromate oxidation correspondent alcohol, be prepared as follows the title compound of embodiment 103-106.
Embodiment 103
1-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-third-1-ketone
Mp.82-85.5 ℃, ultimate analysis C 19H 25NO 2Calculated value: C, 76.74; H, 7.80; N, 4.71; Measured value: C, 76.61; H, 7.94; N, 4.66.
Embodiment 104
1-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-2,2,2-three fluoro-ethyl ketones
1H?NMR(CDCl 3)d?7.06(s，2H)，6.99(s，1H)，2.42(s，3H)，2.30(s，3H)，2.03(s，6H)ppm.
Embodiment 105
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-pyridine-2-base-ketone
1H?NMR(CDCl 3)d?8.72(d，1H)，8.17(d，1H)，7.95(m，1H)，7.52(m，1H)，7.05(s，2H)，6.75(s，1H)，2.25(s，3H)，2.22(s，3H)，2.07(s，6H)ppm.
Embodiment 106
1-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-2-ethyl-Ding-1-ketone
1H?NMR(CDCl 3)d?7.05(s，2H)，6.67(s，1H)，3.98(s，3H)，3.09(m，1H)，2.61(s，3H)，2.06(s，6H)，1.76(m，2H)，1.51(m，2H)，0.92(t，6H)ppm.
Embodiment 107
4-(1-oxyethyl group-2,2,2-three fluoro-ethyls)-3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
Prepare title compound in the following way: make corresponding pure and mild NaH reaction, adopt the iodoethane quenching subsequently.
1H?NMR(CDCl 3)d?6.92(s，1H)，6.87(s，2H)，4.92(m，1H)，3.60(m2H)，2.349s，3H)，2.29(s，3H)，2.26(s，3H)，2.03(s，6H)，1.26(t，3H)ppm.
By corresponding ketone and lithium alkylide or alkyl magnesium reaction, be prepared as follows the title compound of embodiment 108-109.
Embodiment 108
2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-Ding-2-alcohol
1H?NMR(CDCl 3)d?6.86(m，3H)，2.48(s，3H)，2.28(s，3H)，2.21(s，3H)，2.02(s，6H)，1.8-2.1(m，2H)，1.61(s，3H)，0.84(t，3H)ppm.
Embodiment 109
3-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-penta-3-alcohol
1H?NMR(CDCl 3)d?6.87(s，1H)，6.86(s，2H)，2.43(s，3H)，2.28(s，3H0，2.21(s，3H)，2.0-2.2(m，2H)，2.02(s，6H)，1.7-1.9(m，2H)，1.69(brs，1H)，0.8(t，6H)ppm.
Embodiment 110
1-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-hydroxyl-6-methyl-pyridin-4-yl]-2-ethyl-Ding-1-ketone
In THF or methylene dichloride, make 1-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-2-ethyl-Ding-1-ketone BBr 3And BCl 3Reaction, the preparation title compound.
1H?NMR(CDCl 3)d?7.04(s，2H)，7.01(s，1H)，3.26(m，1H)，2.24(s，3H)，2.08(s，6H)，1.80(m，2H)，1.63(m，2H)，0.91(t，6H)ppm.
Embodiment 111
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-niacinamide
In the 4-in anhydrous methylene chloride (1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-nicotinic acid solution, add thionyl chloride.After stirring 1hr, reaction mixture is concentrated to drying.Resistates is dissolved in dry THF and NH3 (g) bubbling is added.Reaction mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer is separated the dry and concentrated faint yellow solid that obtains.1% methyl alcohol of use in chloroform by silica gel chromatography, obtains the title compound into white solid with solid as eluent.mp.85-88℃.1H
NMR(CDCl 3)d?9.69(brs，1H)，8.01(brs，1H)，6.87(s，2H)，6.11(s，1H)，5.48(brs，1H)，3.31(m，1H)，
2.29(s，3H)，2.10(s，3H)，2.07(s，6H)，1.60(m，4H)，0.95(t，6H)ppm.
By similar in appearance to the method for in aforementioned paragraphs, describing, adopt corresponding nicotinic acid or pyridine-5 carboxylic acid derivative to begin and adopt suitable nucleophilic reagent quenching, be prepared as follows the title compound of embodiment 112-118.
Embodiment 112
4-(1-ethyl-propyl group amino)-6, N-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-niacinamide
1H?NMR(CDCl 3)d?9.8(brs，1H)，8.21(brs，1H)，6.88(s，2H)，6.11(s，1H)，3.31(m，1H)，2.92(d，3H)，2.30(s，3H)，2.10(s，3H).2.07(s，6H)，1.60(m，4H)，0.95(t，6H)ppm.
Embodiment 113
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.7(d，1H)，7.9(brs，1H)，7.0(s，2H)，6.2(s，1H)，5.6(brs，1H)，3.7(m，1H)，3.66(m，1H)，3.54(m，1H)，2.07(s，3H)，2.068(s，3H)，2.06(s，3H)，1.7(m，1H)，1.6(m，1H)，0.99(t，3H)ppm
Embodiment 114
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6-methyl-nicotinic acid hydrazide
1H?NMR(CDCl 3)d?9.15(s，1H)，7.04(s，2H)，6.23(s，1H)，3.6-3.8(m，2H)，3.53(m，1H)，2.08(s，6H)，2.05(s，3H)，2.04(s，3H)，1.5-1.8(m，2H)，1.01(t，3H)ppm.
Embodiment 115
2-(4-chloro-2,6-dimethyl-phenoxy group)-N-ethyl-4-(S)-(1-methylol-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.74(d，1H)，8.12(s，1H)，7.05(s，2H)，6.23(s，1H)，3.5-3.8(m，3H)，3.43(m，2H)，2.06(s，9H)，1.8(brs，1H)，1.5-1.7(m，2H)，1.19(t，3H)，1.00(t，3H)ppm.
Embodiment 116
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-methylol-propyl group amino)-6, N-dimethyl-niacinamide
1H?NMR(CDCl 3)d?9.80(d，1H)，8.12(s，1H)，7.04(s，2H)，6.22(s，1H)，3.5-3.8(m，3H)，2.93(d，3H)，2.06(s，9H)，1.8(brs，1H)，1.5-1.7(m，2H)，0.99(t，3H)ppm.
Embodiment 117
2-(4-chloro-2,6-dimethyl-phenoxy group)-N-cyclopentyl-4-(S)-(1-methylol-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.69(d，1H)，8.13(d，1H)，7.04(s，2H)，6.22(s，1H)，4.35(m，1H)，3.4-3.8(m，3H)，2.056(s，9H)，1.4-2.0(m，10H)，0.99(t，3H)ppm.
Embodiment 118
2-(4-chloro-2,6-dimethyl-phenoxy group)-N-cyclopropyl methyl-4-(S)-(1-methylol-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.71(d，1H)，8.24(s，1H)，7.05(s，2H)，6.23(s，1H)，3.5-3.8(m，3H)，3.27(t，2H)，2.08(s，6H)，2.07(s，3H)，1.8(brs，1H)，1.5-1.75(m，2H)，0.99(t，3H)，0.46(m，2H)，0.21(m，2H)ppm.
By the method in embodiment 224, be prepared as follows the title compound of embodiment 232-236.
Embodiment 119
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-niacinamide
Brown solid, mp.204-206 ℃.
Embodiment 120
4-(1-ethyl-propoxy-)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-carboxylic acid's acid amides
Mp.174-176 ℃; Ultimate analysis C 20H 28N 4O 2Calculated value: C, 67.39; H, 7.92; N, 15.72; Measured value: C, 67.90; H, 8.19; N, 14.66.1H NMR (CDCl 3) d 7.95 (s, 1H), 6.89 (s, 2H), 5.58 (s, 1H), 5.4 (m, 1H), 2.28 (s, 3H), 2.25 (s, 3H), 2.15 (s, 6H), 1.75 (m, 4H), 0.96 (t, 6H) ppm.
Embodiment 121
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-cigarette nitrile
1H?NMR(CDCl 3)d?6.85(s，2H)，6.06(s，1H)，4.72(d，1H)，3.36(m，1H)，2.28(s，3H)，2.17(s，3H)，2.09(s，6H)，1.5-1.8(m，4H)，0.96(t，6H)ppm.
Embodiment 122
[4-(1-ethyl-propoxy-)-6-methyl-3-nitro-pyridine-2-yl]-(2,4,6-trimethylammonium-phenyl)-amine
In DMSO, under 130 ℃, by making the reaction of 2-bromine (or chlorine)-4-(1-ethyl-propoxy-)-6-methyl-3-nitro-pyridine and 2, the preparation title compound.Reaction mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer is separated the dry and concentrated roughage that obtains.This material by silica gel chromatography, is obtained the title compound into yellow solid.1H?NMR(CDCl 3)d8.52(s，1H)，6.92(s，2H)，6.12(s，1H)，4.31(m，1H)，2.32(s，3H)，2.24(s，3H)，2.18(s，6H)，1.77(m，4H0，1.01(t，6H)ppm.
Embodiment 123
4-(1-ethyl-propoxy-)-6-methyl-N2-(2,4,6-trimethylammonium-phenyl)-pyridine-2, the 3-diamines
In ethanol, under 50psi, adopt 10%Pd/C, by to the hydrogenation of corresponding 3-nitro-derivative, prepare title compound.Obtain the light gray solid with 97% yield.mp.73-75℃.1H?NMR(CDCl 3)d?6.89(s，2H)，6.18(s，1H)，4.22(m，1H)，3.2(brs，2H)，2.29(s，3H)，2.19(s，6H)，1.7(m，4H)，0.97(t，6H)ppm.
Embodiment 124
2-chloro-N-[4-(1-ethyl-propoxy-)-6-methyl-(2,4,6-trimethylammonium-phenyl amino)-pyridin-3-yl]-ethanamide
In THF, at room temperature, adopt chloroacetyl chloride, Net 3To 4-(1-ethyl-propoxy-)-6-methyl-N2-(2,4,6-trimethylammonium-phenyl)-pyridine-2, the 3-diamines carries out acylations, the preparation title compound.Separate brown solid.Mp.79-82 ℃, ultimate analysis C 22H 30ClN 3O 2Calculated value C, 65.41; H, 7.49; N, 10.40; Measured value: C, 65.56; H, 7.62; N, 10.98.
Embodiment 125
N-butyl-N-ethyl-6-methyl-3-nitro-N-(2,4,6-trimethylammonium-phenyl)-pyridine-2, the 4-diamines
In 140 ℃ of oil baths, (700mg 2.58mmol) spends the night with the mixture heating up of 2 in DMSO with butyl-(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-ethyl-amine.Add the 2 of other 0.75ml and with other 48 hours of the mixture heating up that obtains.Mixture is adopted water, salt solution quenching and adopts ethyl acetate extraction 3 times.Organic layer is separated dry (MgSO 4) be concentrated to drying.After silica gel chromatography, obtain title compound, it is an oily matter.
Embodiment 126
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-nicotinic acid
In the presence of salt of wormwood and copper, in DMF, by heating 2-chloro-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid and trimethylaniline, the preparation title compound.5% methyl alcohol of use in chloroform separates required product as solvent by silica gel column chromatography, obtains brown solid, mp.130-135 ℃.
Embodiment 127
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-nicotinic acid methyl ester
Under refluxing, with 2-chloro-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester, trimethylaniline, salt of wormwood, the mixture heating up of copper in DMF.Mixture is adopted the ammonium chloride quenching and stirs 20min, filter and adopt the ethyl acetate washing by C salt.Filtrate is adopted ethyl acetate extraction.Organic layer is separated, and drying is concentrated to drying.2% methyl alcohol of use in chloroform by silica gel chromatography, obtains being the solid title compound with resistates as eluent.
1H?NMR(CDCl 3)d?8.9(s，1H)，8.0(d，1H)，6.91(s，2H)，5.79s，1H)，3.92(s，3H)，3.37(m，1H)，2.30(s，3H)，2.17(s，3H)，2.10(s，6H)，1.5-1.7(m，4H)，0.96(t，6H)ppm.
Embodiment 128
N4-(1-ethyl-propyl group)-3,6-dimethyl-N2-(2,4,6-trimethylammonium-phenyl)-pyridine-2,4-diamines
Under refluxing, adopt 1M lithium aluminum hydride and aluminum chloride reduction 4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-phenyl amino)-nicotinic acid in ether, the preparation title compound.
1H?NMR(CDCl 3)6.9(s，2H)，6.0(s，1H)，5.4(brs，1H)，3.6(d，1H)，3.3(m，1H)，2.32(s，3H)，2.2(s，3H)，2.15(s，6H)，1.4-1.7(m，4H)，1.0(t，6H)ppm.
Embodiment 129
2-[4-(1-ethyl-propyl group)-6-methyl-N2-(2,4,6-trimethylammonium-phenyl)-pyridin-3-yl methyl]-dimethyl malonate
Mp.136-138 ℃; Ultimate analysis C 26H 37N 3O 4.3/4 H 2O calculated value: C, 66.57; H, 8.27; N, 8.96; Measured value: C, 66.67; H, 7.95; N, 8.88.
Embodiment 130
[2-(4-bromo-2,6-dimethyl-phenyl amino)-4-(1-ethyl-propyl group amino)-6-methyl-pyridin-3-yl]-methyl alcohol
Under refluxing, in THF, by using BH 3.DMS reduce corresponding nicotinic acid derivates, the preparation title compound.The standard treatment step obtains the title compound into the white foam shape.
1H?NMR(CDCl 3)7.15(s，2H)，6.2(brs，1H)，5.92(s，1H)，4.479m，1H)，4.43(s，2H)，3.25(m，1H)，2.17(s，3H)，2.10(s，6H)，1.58(m，2H)，1.47(m，2H)，0.90(t，6H)ppm.
Embodiment 131
N2-(2,4-two chloro-phenyl)-N4-(1-ethyl-propyl group)-3,6-dimethyl-pyridine-2,4-diamines
By the method for in embodiment 33, describing, the preparation title compound.
1H?NMR(CDCl 3)d?7.79(dd，1H)，7.30(d，1H)，7.10(dd，1H)，6.53(brs，1H)，6.13(s，1H)，3.79(d，1H)，3.2-3.4(m，1H)，2.36(s，3H)，1.92(s，3H)，1.4-1.6(m，4H)，0.93(t，6H)ppm.
Embodiment 132
[2-(2,4-two chloro-phenyl aminos)-4-(1-ethyl-propyl group amino)-6-methyl-pyridin-3-yl]-methyl alcohol
Under refluxing, in THF, by using BH 3.DMS reduce corresponding nicotinic acid derivates, the preparation title compound.1H NMR (CDCl 3) d 7.22 (d, 1H), 7.07 (d, 1H), 7.00 (d, 1H), 6.10 (s, 1H), 5.7 (brs, 1H), 4.4 (s, 2H), 3.3 (m, 1H), 2.35 (s, 3H), 2.02 (s, 3H), 1.4-1.6 (m, 4H), 0.92﹠amp; 0.91 (two cover t, 6H) ppm.
Embodiment 133
2-[6-methyl-3-nitro-2-(2,4,6-trimethylammonium-phenylamino oxygen base)-pyridin-4-yl amino]-Ding-1-alcohol
In DMSO, under 130 ℃, by heating 2-[6-methyl-3-nitro-2-chloro-pyridin-4-yl amino]-the pure and mild trimethylaniline of Ding-1-, the preparation title compound.
1H?NMR(CDCl 3)d?9.38(brs，1H)，6.93(s，3H).3.7-3.8(m，3H)，2.30(s，3H)，2.12(s，6H)，1.8(m，1H)，1.65(m，1H)，1.02(t，3H)ppm
Embodiment 134
2-[4-(1-ethyl-propyl group amino)-2-methyl-6-(2,4,6-trimethylammonium-phenoxy group)-pyrimidine-5-yl]-ethyl propionate
1H?NMR(CDCl 3)d?6.85(s，2H)，5.16(d，1H)，4.49(q，1H)，4.0-4.2(m，3H)，2.289s，3HO.2.20(s，3H)，2.06(s，6H)，1.4-1.7(m，4H)，1.44(d，3H)，1.21(t，3H)，0.93(t，3H)，0.87(t，3H)ppm.
Embodiment 135
[3-amino methyl-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(1-ethyl-propyl group)-amine
Prepare title compound by method similar in appearance to embodiment 75.Mp.117-119 ℃; Ultimate analysis C 21H 31N 3O.1/3 H 2O calculated value: C, 72.58; H, 9.18; N, 12.09; Measured value: C, 72.93; H, 9.28; N, 12.02.
The following title compound for preparing embodiment 136-138 in the following way: in benzene with 4-(1-ethyl-propyl group amino)-6-methyl-2-(4-halogen-26-dimethyl-phenoxy group)-pyridin-3-yl]-reaction of methyl alcohol and thionyl chloride, be concentrated to drying, at room temperature in DMSO, react subsequently with potassium cyanide.
Embodiment 136
[2-(4-bromo-2,6-dimethyl-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-pyridin-3-yl]-acetonitrile
1H?NMR(CDCl 3)d?7.2(s，2H)，6.1(s，1H)，3.82(d，1H)，3.7(s，2H)，3.34(m，1H)，2.1(s，3H)，2.03(s，6H)，1.45-1.7(m，4H)，0.99(t，6H)ppm.
Embodiment 137
[2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-pyridin-3-yl]-acetonitrilehydrochlorate
1H?NMR(CDCl 3)d?7.08(s，2H)，6.2(s，1H)，4.92(d，1H)，3.45(m，1H)，2.71(s，3H)，2.549m，2H)，2.14(s，6H)，1.7(m，2H)，1.40-1.6(m，4H)，0.95(t，6H)ppm.
Embodiment 138
[6-(1-ethyl-propoxy-)-2-methyl-pyrimidine-4-yl]-(2,4,6-trimethylammonium-phenyl)-amine
MP.149-151 ℃, ultimate analysis C 20H 26N 4O calculated value: C, 72.81; H, 8.68; N, 13.41; Measured value: C, 72.70; H, 8.86; N, 13.14
Embodiment 139
2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
In 160-170 ℃ of oil bath, by heating corresponding nicotinic acid derivates, the preparation title compound.1H?NMR(CDCl 3)d?7.05(s，2H)，6.09(s，1H)，5.35(s，1H)，4.43(s，1H)，3.68(m，1H)，3.64(m，1H)，3.29(m，1H)，2.30(s，3H)，2.09(s，6H)，1.60(m，1H)，1.47(m，1H)，0.89(t，3H)ppm.
Embodiment 140
[3-amino methyl-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridine-4-(S)-yl]-(1-chloromethyl-propyl group)-amine
Prepare title compound in the following way: in benzene with 2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-pyridine-4-(S)-Ji amino]-reaction of the pure and mild thionyl chloride of Ding-1-, be concentrated to drying, subsequently at room temperature with NH 3(g) reaction.After standard treatment step and silica gel column chromatography, obtain title compound.1H?NMR(CDCl 3)d7.00(s，2H)，6.3(brs，1H)，6.07(s，1H)，4.0-4.2(m，2H)，3.9(brs，2H)，3.5-3.8(m，3H)，2.12(s，3H)，2.03(s，6H)，1.6-1.9(m，2H)，1.00(t，3H)ppm
The following title compound for preparing embodiment 254 and 255 in the following way: in benzene with 2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-pyridine-4-(S)-Ji amino]-the pure and mild thionyl chloride reaction of Ding-1-, be concentrated to drying, subsequently at room temperature in THF with the reaction of suitable amine.After standard treatment step and silica gel column chromatography, obtain title compound.
Embodiment 141
2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-3-methylamino methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.01(s，2H)，6.14(s，1H)，4.55(brs，1H)，3.6-3.8(m，2H)，3.4(m，1H)，2.6(s，3H)，2.11(s，3H)，2.02(brs，6H)，1.65(m，2H)，0.97(t，3H)ppm.
Embodiment 142
2-[3-methylamino-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?6.999s，2H)，6.10(s，1H)，4.4.00(Abq，2H)，3.5-3.75(m，2H)，3.4(m，1H)，2.73(brs，4H)，2.08(s，3H)，2.00(s，6H)，1.58(m，4H)，0.94(t，3H)ppm.
In methylene dichloride or chloroform, at room temperature, carry out the bromination or the chlorination of 2-[2-(substituent phenoxy)-6-methyl-pyridine-4-alkylamine by adopting NBS or NCS, be prepared as follows the title compound of embodiment 143-149.
Embodiment 143
[3-bromo-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(1-ethyl-propyl group)-amine
1H?NMR(CDCl 3)d?6.85(s，2H)，6.04(s，1H)，4.62(d，1H)，3.33(m，1H)，2.27(s，3H)，2.13(s，3H)，2.08(s，6H)，1.5-1.7(m，2H)，0.95(t，3H)ppm.
Embodiment 144
2-[3,5-two bromo-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridin-4-yl amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.02(s，2H)，4.34(m，1H)，3.6-3.8(m，2H)，2.30(s，3H)，2.05(s，6H)，1.5-1.8(m，2H)，0.98(t，3H)ppm.
Embodiment 145
2-[3-bromo-6-(4-chloro-2,6-dimethyl-phenoxy group)-2-methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.05(s，2H)，5.62(s，1H)，4.86(d，1H)，3.55-3.7(m，2H)，3.3(m，1H)，2.428(s，3H)，2.09(s，6H)，1.4-1.7(m，3H)，0.91(t，3H)ppm.
Embodiment 146
2-[3-bromo-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.02(s，2H)，6.14(s，1H)，4.81(d，1H)，3.6-3.8(m，2H)，3.45(m，1H)，2.12(s，3H)，2.08(s，6H)，1.5-1.8(m，2H)，1.00(t，3H)ppm.
Embodiment 147
2-[3-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.02(s，2H)，6.18(s，1H)，4.76(d，1H)，3.6-3.8(m，2H)，3.45(m，1H)，2.13(s，3H)，2.07(s，6H)，1.5-1.8(m，2H)，0.99(t，3H)ppm.
Embodiment 148
2-[3,5-two chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridin-4-yl amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.03(s，2H)，4.34(m，1H)，3.6-3.8(m，2H)，2.40(s，3H)，2.05(s，6H)，1.5-1.8(m，2H)，0.99(t，3H)ppm.
Embodiment 149
2-[3-chloro-6-(4-chloro-2,6-dimethyl-phenoxy group)-2-methyl-pyridine-4-(S)-Ji amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.05(s，2H)，5.66(s，1H)，4.86(brs，1H)，3.5-3.8(m，2H)，3.3(m，1H)，2.38(s，3H)，2.09(s，6H)，1.4-1.7(m，3H)，0.91(t，3H)ppm.
Embodiment 150
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(4-ethyl-2-oxo-oxazolidines-3-yl)-6-methyl-cigarette nitrile
In THF, by making 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid and triphosgene/NEt 3Reaction response, the preparation title compound.1HNMR(CDCl 3)d?7.18(s，1H)，7.06(s，2H)，5.00(m，1H)，4.64(t，1H)，4.23(dd，1H)，2.339s，3H)，2.08(s，6H)，1.5-1.8(m，2H)，0.949t，3H)ppm.
Embodiment 151
2-(2,4-dimethoxy-phenyl amino)-4-(1-methoxymethyl-propoxy-)-6-methyl-nicotinic acid
1H?NMR(CDCl 3)d?8.3(brs，1H)，6.5(m，3H)，6.26(s，1H)，4.66(m，1H)，3.92(s，3H)，3.85(s，3H)，3.66(m，2H)，3.43(s，3H)，2.52(s，3H)，1.91(m，2H)，1.07(t，3H)ppm.
Embodiment 152
4-(1-ethyl-propoxy-)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-nitrile
1H?NMR(CDCl 3)d?6.92(s，2H)，6.45(s，1H)，5.22(m，1H)，2.29(s，6H)，2.16(s，6H)，1.70(m，4H)，0.93(t，6H)ppm.
Embodiment 153
N-(1-ethyl-propyl group)-2,5-dimethyl-N '-(2,4,6-trimethylammonium-phenyl)-pyrimidine-4,6-diamines
1H?NMR(CDCl 3)d?8.9(s，1H)，6.85(s，2H)，4.95(d，1H)，4.21(m，1H)，2.5(s，3H)，2.25(s，3H)，2.13(s，6H)，1.4-1.7(m，4H)，1.3(s，3H)，0.85(t，6H)ppm
Embodiment 154
5-chloro-N4-(1-ethyl-propyl group)-2-methyl-N6-(2,4,6-trimethylammonium-phenyl)-pyrimidine-4, the 6-diamines
1H?NMR(CDCl 3)d?6.85(s，2H)，6.0(s，1H)，4.D(m，1H)，4.2(m，1H)，2.3(s，3H)，2.22(，3H)，2.17(s，6H)，1.4-1.70(m，4H)，0.97(t，6H)ppm.
Embodiment 155
5-bromo-N-(1-ethyl-propyl group)-2-methyl-N '-(2,4,6-trimethylammonium-phenyl)-pyrimidine-4, the 6-diamines
MP.117-119 ℃, ultimate analysis C 19H 21BrN 4Calculated value: C, 58.31; H, 6.95; N, 14.32; Measured value: C, 58.43; H, 7.08; N, 14.23.
Embodiment 156
4-(1-ethyl-propyl group amino)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-formic acid
1H?NMR(CDCl 3)d?12.2(brs，1H)，11.1(brs，1H)，?6.84(s，2H)，4.18(m，1H)，2.38(s，3H)，2.18(s，3H)，2.15(s，6H)，1.56(m，4H)，0.90(t，6H)ppm.
Embodiment 157
[4-(cyclopropyl methyl-propyl group-amino)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-yl]-methyl alcohol
1H?NMR(CDCl 3)d?7.49s，2H)，4.95(s，2H)，4.92(s，1H)，3.28(brs，4H)，2.359s，3H)，1.54(m，2H)，0.95(m，1H)，0.81(t，3H)，0.44(m，2H)，0.19(m，2H)ppm.
Embodiment 158
6-(1-ethyl-propoxy-)-2, N5, N5-trimethylammonium-N4-(2,4,6-trimethylammonium-phenyl)-pyrimidine-4,5-diamines
Prepare title compound in the following way: in THF, adopt two (trimethyl silyl) acid amides lithiums to 6-(1-ethyl-propoxy-)-2-methyl-N4-(2,4,6-trimethylammonium-phenyl)-and pyrimidine-4, the 5-diamines methylates, and adopts the methyl iodide quenching subsequently.
1H?NMR(CDCl 3)d?7.35(s，1H)，6.90(s，2H)，5.16(m，1H)，2.73(s，6H)，2.29(s，3H)，2.27(s，3H)，2.18(s，6H)，1.6-1.8(m，4H)，0.96(t，6H)?ppm.
Embodiment 159
[5-bromo-6-(1-ethyl-propoxy-)-2-methyl-pyrimidine-4-yl]-(2,4,6-trimethylammonium-phenyl)-amine
Under refluxing, in THF, by [5-bromo-6-(1-ethyl-propoxy-)-2-methyl-pyrimidine-4-yl]-(2,4,6-trimethylammonium-phenyl)-amine and 3-amylalcohol/NaH reaction are spent the night the preparation title compound.After standard processing and purifying, obtain title compound with white solid.mp.94-96℃.1H?NMR(CDCl 3)d?6.91(s，2H)，6.41(s，1H)，5.13(m，1H)，2.29(s，3H)，2.26(，3H)，2.17(s，6H)，1.70(m，4H)，0.95(t，6H)ppm.
Embodiment 160
4-(1-ethyl-propoxy-)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-formic acid
Under-78 ℃, in the n-BuLi solution in THF, be added in the solution of [5-bromo-6-(1-ethyl-propoxy-)-2-methyl-pyrimidine-4-yl]-(2,4,6-trimethylammonium-phenyl)-amine among the THF.After stirring 10 minutes, add CO down at-78 ℃ 2(g) and under this temperature stirred 1 hour, be warmed up to room temperature then gradually.The mixture that obtains is adopted the water quenching and be adjusted to pH2-3 and the employing chloroform extraction.Organic layer is separated, and drying is concentrated to drying.Resistates is obtained being the solid title compound by silica gel chromatography.Mp.118-120 ℃, ultimate analysis C 20H 27N 3O 3Calculated value: C, 67.20; H, 7.61; N, 11.76; Measured value: C, 67.25; H, 7.87; N, 11.48.
Embodiment 161
[4-(1-ethyl-propoxy-)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-yl]-methyl alcohol
In the 4-in dry THF (1-ethyl-propoxy-)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-formic acid solution, add BH 3.DMS.With the mixture heating under refluxing that obtains.Mixture is adopted rare HCl quenching and stirred 30 minutes, pH regulator to 7.5-8.5, is adopted ethyl acetate extraction then.Organic layer is separated the dry and concentrated roughage that obtains.Roughage is obtained being the solid title compound by silica gel chromatography.Mp.121-123 ℃, ultimate analysis C 20H 29N 3O 2Calculated value C, 69.94; H, 8.51; N, 12.23; Measured value: C, 69.73; H, 8.47; N, 11.99.
Embodiment 162
[6-(1-ethyl-propoxy-)-5-methoxymethyl-2-methyl-pyrimidine-4-yl]-(2,4,6-trimethylammonium-phenyl)-amine
Prepare title compound in the following way:, adopt the MeI quenching subsequently with [4-(1-ethyl-propoxy-)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-yl]-methyl alcohol and NaH reaction.
1H?NMR(CDCl 3)d?7.0(s，1H)，6.89(s，2H)，5.12(m，1H)，4.62(s，2H)，3.33(s，3H)，2.28(s，3HO，2.27(s，3H)，2.14(s，6H)，1.66(m，4H)，0.91(t，6H)ppm.
Embodiment 163
[5-amino methyl-6-(1-ethyl-propoxy-)-2-methyl-pyrimidine-4-yl]-(2,4,6-trimethylammonium-phenyl)-amine
In [4-(1-ethyl-propoxy-)-2-methyl-6-(2,4,6-trimethylammonium-phenyl amino)-pyrimidine-5-yl]-methanol solution in anhydrous methylene chloride, add thionyl chloride.After stirring 1 hour, reaction mixture is concentrated to drying.Resistates is dissolved in dry THF and with NH 3(g) bubbling adds.Reaction mixture is adopted the water quenching and adopts ethyl acetate extraction.To react by standard step processing and purifying and obtain title compound.
1H?NMR(CDCl 3)d?8.50(s，1H)，6.88(s，2H)，5.08(m，1H)，3.97(s，2H)，2.279s，3H)，2.25(s，3H)，2.159s，6H)，1.74(brs，2H)，1.65(m，4H)，0.91(t，6H)ppm.
Embodiment 164
7-(1-ethyl-propoxy-)-5-methyl-3-(2,4,6-trimethylammonium-phenyl)-3H-imidazo [4,5-b] pyridine-2-base amine
In acetonitrile, at room temperature, by with 4-(1-ethyl-propyl group)-6-methyl-N2-(2,4,6-trimethylammonium-phenyl)-pyridine-2,3-diamines and BrCN reaction are spent the night, the preparation title compound.Mixture is adopted the water quenching and adopt full sodium bicarbonate to be adjusted to pH8.0 and employing ethyl acetate extraction.Organic layer is separated the dry and concentrated roughage that obtains.Material is obtained title compound into white solid by silica gel chromatography.mp.159-161℃.1H?NMR(CDCl 3)d?7.05(s，2H)，6.5(s，1H)，4.6(m，1H)，4.3(m，2H)，2.45(s，3H)，2.35(s，3H)，2.0(s，6H)，1.7(m，4H)，1.0(t，6H)ppm.
Embodiment 165
7-(1-ethyl-propoxy-)-5-methyl-3-(2,4,6-trimethylammonium-phenyl amino)-3H-imidazo [4,5-b] pyridine
Under refluxing, use Dean-Stark equipment, with 4-(1-ethyl-third amino)-6-methyl-N2-(2,4,6-trimethylammonium-phenyl)-pyridine-2,3-diamines, trimethyl orthoformate, the tosic acid-hydrate mixture heating up in toluene 24 hours.Under refluxing, mixture heating up is spent the night.Mixture is adopted water, saturated NaHCO 3Ethyl acetate extraction is adopted in quenching.Organic layer is separated dry (MgSO 4) be concentrated to drying.After purifying, separate title compound.Ultimate analysis C 21H 29N 3O.1/4H 2O calculated value C, 73.76; H, 8.10; N, 12.29; Measured value: C, 73.22; H, 7.96; N, 12.42.
Embodiment 166
7-(1-ethyl-propoxy-)-5-methyl-3-(2,4,6-trimethylammonium-phenyl amino)-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also
In THF, at room temperature, by making 4-(1-ethyl-propoxy-)-6-methyl-N2-(2,4,6-trimethylammonium-phenyl)-pyridine-2,3-diamines and triphosgene, NEt 3The prepared in reaction title compound.Separate white solid.mp.184-186℃。Ultimate analysis C 21H 27N 3O 2Calculated value C, 71.36; H, 7.70; N, 11.89; Measured value: C, 71.09; H, 7.75; N, 11.63.
Embodiment 167
7-(1-ethyl-propoxy-)-1,5-dimethyl-3-(2,4,6-trimethylammonium-phenyl)-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also
Prepare title compound in the following way: with 7-(1-ethyl-propoxy-)-5-methyl-3-(2,4,6-trimethylammonium-phenyl)-1,3-dihydro-imidazol-also [4,5-b] pyridin-2-ones and two (trimethyl silyl) acid amides lithium reaction, adopt the methyl iodide quenching subsequently.Mp.151-153 ℃. ultimate analysis C 22H 29N 3O 2.1/4H 2O calculated value C, 71.03; H, 7.99; N, 11.30; Measured value: C, 71.29; H, 8.01; N, 11.03.
Embodiment 168
(1-ethyl-propyl group)-[5-methyl-3-(2,4,6-trimethylammonium-phenyl)-3H-imidazo [4,5-b] pyridine-7-yl]-amine
Under refluxing, use Dean-Stark equipment, with N-4-(1-ethyl-propyl group)-6-methyl-N-2-(2,4,6-trimethylammonium-phenyl)-and pyridine-2,3,4-triamine (250mg, 0.77mmol), trimethyl orthoformate (0.081g, 0.766mmol), the mixture heating up of tosic acid monohydrate (0.01g) in benzene 24 hours.Remove benzene and add toluene and adding excessive trimethyl orthoformate (0.084ml) in reaction mixture.With mixture heated overnight under refluxing.Mixture is adopted water, saturated NaHCO 3Ethyl acetate extraction is adopted in quenching.Organic layer is separated dry (MgSO 4) be concentrated to drying.After purifying, be separated into the title compound of white crystal, mp 78-80 ℃.
Embodiment 169
[2,5-dimethyl-3-(2,4,6-trimethylammonium-phenyl)-3H-imidazo [4,5-b] pyridine-7-yl]-(1-ethyl-propyl group)-amine
Under refluxing, use Dean-Stark equipment, with N-4-(1-ethyl-propyl group)-6-methyl-N-2-(2,4,6-trimethylammonium-phenyl)-and pyridine-2,3,4-triamine (250mg, 0.77mmol), trimethyl orthoformate (0.184g, 1.532mmol), the mixture heating up of tosic acid monohydrate (0.01g) in toluene 3 hours.Mixture is adopted water, salt solution quenching, adopt ethyl acetate extraction.Organic layer is separated dry (MgSO 4) be concentrated to drying.After purifying, be separated into the title compound of white crystal.Mp.101-103 ℃. ultimate analysis C 22H 30N 4Calculated value C, 75.39; H, 8.63; N, 15.98; Measured value, C, 75.44; H, 8.95; N, 15.95.
Embodiment 170
N7-(1-ethyl-propyl group)-5-methyl-3-(2,4,6-trimethylammonium-phenyl)-3H-imidazo [4,5-b] pyridine-2, the 7-diamines
In acetonitrile, at room temperature, by making N4-(1-ethyl-propyl group)-6-methyl-N-2-(2,4,6-trimethylammonium-phenyl)-pyridine-2,3,4-triamine and BrCN reaction, preparation title compound.Mixture is adopted the water quenching and adopts saturated sodium bicarbonate to be adjusted to pH8.0 and to adopt ethyl acetate extraction.Organic layer is separated the dry and concentrated roughage that obtains.Material is obtained title compound into brown solid by silica gel chromatography.Mp.158-160 ℃; Ultimate analysis C 21H 29N 51/4H 2O calculated value C, 70.85; H, 8.35; N, 19.67; Measured value: C, 71.07; H, 8.30; N, 19.63.
Embodiment 171
6-(1-ethyl-propyl group amino)-2,7-dimethyl-9-(2,4,6-trimethylammonium-phenyl)-7,9-dihydro-purine-8-ketone
In THF, by adopting two (trimethyl silyl) acid amides lithiums to 6-(1-ethyl-propyl group amino)-2-methyl-9-(2,4,6-trimethylammonium-phenyl)-7,9-dihydro-purine-8-ketone methylates, and adopts the methyl iodide quenching subsequently, the preparation title compound.
1H?NMR(CDCl 3)d?6.98(s，2H)，4.45(d，1H)，4.3(m，1H)，3.7(s，3H)，2.4(s，3H)，2.3(s，3H)，2.1(s，6H)，1.5-1.8(m，4H)，1.0(t，6H)ppm.
Embodiment 172
6-(1-ethyl-propoxy-)-2,7-dimethyl-9-(2,4,6-trimethylammonium-phenyl)-7,9-dihydro-purine-8-ketone
In THF, by adopting two (trimethyl silyl) acid amides lithiums to 6-(1-ethyl-propoxy-)-2-methyl-9-(2,4,6-trimethylammonium-phenyl)-7,9-dihydro-purine-8-ketone methylates, and adopts the methyl iodide quenching subsequently, the preparation title compound.
1H?NMR(CDCl 3)d7.00(s，2H)，5.31(m，1H)，3.66(s，3H).2.479s，3H)，2.33(s，3H)，2.06(s，6H)，1.79(m，4H)，1.01(t，6H)ppm.
Embodiment 173
[2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.71(d，1H)，6.57(s，2H)，?6.21(s，1H)，3.76(s，3H)，?3.59(m，1H)，3.48(m，1H)，3.45(m，1H)，3.37(s，3H)，2.13(s，3H)，2.08(s，6H)，1.6-1.8(m，4H)，0.86(t，3H)ppm.
Embodiment 174
(1-ethyl-propyl group)-[2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?6.64(s，2H)，6.12(s，1H)，3.82(s，3H)，3.36(m，1H)，2.26(s，3H)，2.13(s，6H)，2.10(s，3H)，1.5-1.8m，4H)，0.99(t，6H).
Embodiment 175
2-[2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl amino]-Ding-1-alcohol
1H?NMR(CDCl 3)d?6.64(s，2H)，6.13(s，1H)，4.10(m，1H)，3.76(s，3H)，3.7-3.8(m，21H)，3.57(m，1H)，2.21(s，3H)，2.19(s，6H)，2.12(s，3H)，1.6-1.8(m，2H)，1.04(t，3H)ppm.
Embodiment 176
Sec-butyl-[3-methoxyl group-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?6.64(s，2H)，6.13(s，1H)，4.51(d，1H)，3.92(s，3H)，3.82(s，3H)，3.469m，1H)，2.18(s，3H)，2.15(s，6H)，1.60(m，2H)，1.26(d，3H)，1.00(t，3H)ppm.
Embodiment 177
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(4-ethyl-oxazolidines-3-yl)-3,6-dimethyl-pyridine
1H?NMR(CDCl 3)d?7.07(s，2H)，6.36(s，1H)，4.98(m，1H)，4.78(m，1H)，4.23(m，1H)，3.83(m，1H)，3.71(m，1H)，2.28(s，3H)，2.20(s，3H)，2.09(s，6H)，1.81(m，1H)，1.58(m，1H)，0.98(t，3H)ppm.
Embodiment 178
4-(4-ethyl-oxazolidines-3-yl)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridine
1H?NMR(CDCl 3)d?6.65(s，2H)，6.36(s，1H)，4.98(m，1H)，4.77(m，1H)，4.23(m，1H)，3.83(s，3H)，3.71(m，1H)，)，2.29(s，3H)，2.22(s，3H)，2.119(s，6H)，1.82(m，1H)，1.56(m，1H)，0.99(t，3H)ppm
Embodiment 179
2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-N%4﹠amp;-(1-methoxymethyl-propyl group)-6-methyl-pyridine-3, the 4-diamines
1H?NMR(CDCl 3)d?6.64(s，2H)，6.16(s，1H)，4.3(m，1H)，3.82(s，3H)，3.6-3.8(m，2H).3.42(s，3H)，3.2(brs，2H)，2.18(s，3H)，2.13(s，6H)，1.6-1.8(m，2H)，1.03(t，3H)ppm.
Embodiment 180
3-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methylol-6-methyl-pyridin-4-yl amino]-penta-2-alcohol
1H?NMR(CDCl 3)d?7.01(s，2H)，6.16(s，1H)，5.19(d，1H)，4.94(m，2H)，3.88(m，1H)，3.27(m，1H)，2.11(s，3H)，2.05(s，6H)，1.73(m，1H)，1.57(m，1H)，1.24(d，3H)，0.97(t，3H)ppm.
Embodiment 181
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-oxo-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.63(d，1H)，7.01(s，2H)，5.90(s，1H)，3.95(m，1H)，3.90(s，3H)，2.08(s，3H)，2.05(s，3H)，2.03(s，6H)，1.8-2.0(m，2H)，1.00(t，3H)ppm.
Embodiment 182
3-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxymethyl-6-methyl-pyridin-4-yl amino]-penta-2-alcohol
1H?NMR(CDCl 3)d?7.08(s，2H)，6.21(s，1H)，5.40(brs，1H)，4.83(q，2H)，3.91(m，1H)，3.40(s，3H)，3.33(m，1H)，2.20(s，3H)，2.10(s，6H)，1.78(m，1H)，1.58(m，1H)，1.29(d，3H)，1.01(t，3H)ppm.
Embodiment 183
3-[2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl amino]-penta-2-alcohol
1H?NMR(CDCl 3)d?6.66(s，2H)，6.27(s，1H)，4.05(m，1H)，3.82(s，3H)，3.38(m，1H)，2.35(s，3H)，2.21(s，3H)，2.14(s，6H)，1.6-1.9(m，2H)，1.30(m，3H)，1.01(t，3H)ppm.
Embodiment 184
4-sec-butyl amino-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.01(d，1H)，6.58(s，2H)，6.06(s，1H)，3.85(s，3H)，3.77(s，3H)，2.10(s，3H)，2.07(s，6H)，1.21(d，3H0，0.97(t，3H)ppm.
Embodiment 185
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-hydroxy-2-methyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.28(d，1H)，7.06(s，2H)，6.32(s，1H)，3.92(s，3H)，3.41(m，1H)，2.14(s，3H)，2.12(s，6H)，1.91(m，1H)，1.44(m，1H)，1.33(s，3H)，1.30(s，3H0，0.99(s，3H)ppm.
Embodiment 186
4-(1-methylol-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.13(d，1H)，6.63(s，2H)，6.21(s，1H)，3.91(s，3H0，3.82(s，3HO，3.81(m，2H)，3.59(m，1H)，2.16(s，3H)，2.12(s，6H)，1.6-1.859m，2H)，1.05(t，3H)ppm.
Embodiment 187
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-3-methyl sulfenyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
In 134 ℃ of oil baths, with 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-chloro-6-methyl-nicotinic acid methyl ester and the mixture heating up 3hr of L-methioninol in N-N-methyl-2-2-pyrrolidone N-(NMP).Standard treatment step and purifying provide title compound.1H
NMR(CDCl 3)d?8.25(d，1H)，7.02(s，2H)，6.30(s，1H)，3.85(s，3H)，3.6-3.9(m，3H)，2.5-2.7(m，2H)，
2.14(s，3H)，2.10(s，3H)，2.06(s，6H)，1.8-2.1(m，2H)ppm.
Embodiment 188
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(S)-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester
Under-10 ℃, in dry THF 3-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxycarbonyl-6-methyl-pyridin-4-yl amino]-4-hydroxyl-butyl)-add t-BuOK in dimethyl-sulfonium iodide solution.Mixture is stirred down at-10 ℃, run out of up to all starting raw materials.Standard treatment step and silica gel purification obtain title compound.
1H?NMR(CDCl 3)d?8.25(d，1H)，7.01(s，2H)，6.05(s，1H)，4.11(m，1H)，3.9-4.1(m，2H).3.8-3.9(m，1H)，3.86(s，3H)，3.73(m，1H)，2.2-2.4(m，1H)，2.11(s，3H)，2.05(s，6H)，1.95(m，1H)ppm.
Embodiment 189
3-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxycarbonyl-6-methyl-pyridin-4-yl amino]-4-hydroxyl-butyl }-dimethyl-sulfonium iodide
Under refluxing, in sealed tube, with 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-3-methyl sulfenyl-propyl group amino)-6-methyl-nicotinic acid methyl ester and the mixture heating up of MeI in EtOAc.Mixture is concentrated to drying and adopts the ether development, obtain title compound.
1H?NMR(CD 3OD)d?7.11(s，2H)，6.61(s，1H)，4.00(m，1H)，3.86(s，3H)，3.6-3.9(m，3H)，2.95(d，6H)，2.5-2.7(m，2H)，2.22(s，3H)，2.07(s，6H)，1.8-2.1(m，2H)ppm.
Embodiment 190
4-(1-methylol-3-methyl sulfenyl-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.15(d，1H)，6.58(s，2H)，6.28(s，1H)，3.85(s，3H)，3.76(s，3H)，3.6-3.9(m，3H)，2.5-2.7(m，2H)，2.12(s，3H)，2.09(s，3H)，2.07(s，6H)，1.8-2.1(m，2H)ppm.
Embodiment 191
4-(1-methylol-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6, N-dimethyl-niacinamide
1H?NMR(CDCl 3)d?9.84(d，1H)，8.31(m，1H)，6.66(s，2H)，6.29(s，1H)，3.81(s，3H)，3.5-3.9(m，3H)，2.98(d，3H)，2.15(s，3H)，2.12(s，6H)，1.6-1.8(m，2H)，1.05(t，3H)ppm.
Embodiment 192
4-sec-butyl amino-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6, N-dimethyl-niacinamide
1H?NMR(CDCl 3)d?9.77(brs，1H)，8.22(brs，1H)，6.61(s，2H)，6.11(s，1H)，3.78(s，3H)，3.45(m，1H)，2.93(d，3H)，2.10(s，3H)，2.07(s，6H)，1.5-1.7(m，2H)，1.23(m，3H)，0.98(t，3H)ppm.
Embodiment 193
2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.28(d，1H)，6.63(s，2H)，6.09(s，1H)，4.15(m，1H)，3.98-4.1(m，2H)，3.8-3.98(m，1H)，3.90(s，3H)，3.81(s，3H)，3.76(m，1H)，2.32-2.36(m，1H)，2.19(s，3H)，2.11(s，6H)，1.95(m，1H)ppm.
Embodiment 194
4-sec-butyl amino-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.74(ds，1H)，8.05(brs，1H)，6.65(s，2H)，6.16(s，1H)，5.55(brs，1H)，3.83(s，3H)，3.51(m，1H)，2.16(s，3H)，2.12(s，6H)，1.5-1.7(m，2H)，1.26(d，3H)，1.02(t，3H)ppm.
Following embodiment 195-256 relates to other compound of general formula I of the present invention, wherein R 4Be-COOCH 3:
By the method for in embodiment 13, describing, adopt 4-chloro-2-(phenoxy group of replacement)-6-methyl-nicotinic acid methyl ester and suitable amine to begin, the following title compound of preparation embodiment 195-209:
Embodiment 195
2-(4-oxyethyl group-2,6-dimethyl-phenoxy group)-4-(1-methylol-3-methyl sulfenyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.35(d，1H)，6.60(s，2H)，6.41(s，1H)，4.03(q，2H)，3.90(m，1H)，3.86(s，3H)，3.75(m，2H)，2.60(，2H)，2.21(s，3H)，2.11(s，3H)，2.09(s，6H)，2.03(m，1H)，1.88(m，1H)，1.40(t，1.39)ppm
Embodiment 196
4-(1-methylol-3-methyl sulfenyl-propyl group amino)-2-[4-(2-methoxyl group-oxyethyl group)-2,6-dimethyl-phenoxy group]-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.38(d，1H)，6.64(s，2H)，6.42(s，1H)，4.10(m，2H)，3.92(m，1H)，3.86(s，3H)，3.73(m，5H)，3.45(s，3H)，2.60(m，2H)，2.22(s，3H)，2.13(s，3H)，2.09(s，6H)，1.87(m，2H)ppm
Embodiment 197
2-(2,6-dimethyl-4-trifluoromethoxy-phenoxy group)-4-(1-methylol-3-methyl sulfenyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.21(br?d，1H，J＝8Hz)，6.91(s，2H)，6.28(s，1H)，3.87(s，3H)，3.84(m，1H)，3.70-3.76(m，2H)，2.53-2.68(m，2H)，2.11(m，12H)，1.88-2.06(m，2H).
Embodiment 198
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(R)-(1-methylol-3-methyl sulfenyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
C 21H 27ClN 2O4s：MS：M+1[439.2]
Embodiment 199
2-(4-chloro-2,6-dimethoxy-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.29(d，1H，J+8Hz)，6.63(s，2H)，6.23(s，1H)，3.86(s，3H)，3.74(s，6H)，3.69-3.72(m，1H)，3.62-3.66(m，1H)，3.52-3.58(m，1H)，2.83(s，1H)，2.13(s，3H)，1.70-1.77(m，1H)，1.54-1.61(m，1H)，0.99(t，3H，J＝7Hz)
13C?NMR(CDCl 3)d.169.75，158.50，153.43，130.15，106.96，101.49，64.67，56.95，56.12，56.05，52.18，46.05，24.92，10.67
Embodiment 200
2-(4-chloro-2,6-dimethoxy-phenoxy group)-4-(1-methylol-3-methyl sulfenyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.39(br?d，1H，J＝7Hz)，6.64(s，2H)，6.30(s，1H)，3.87(s，3H)，3.75(s，6H)，3.36-3.39(m，1H)，2.84(s，1H)，2.53-2.70(m，2H)，2.35-2.39(m，1H)，2.14(d，3H，J＝9Hz)，1.94-2.07(m，2H)，1.79-1.92(m，2H)ppm.APCI+m/z＝471.2(M+1)，473.2(M+3)
Embodiment 201
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-[(1-methylol-propyl group)-methyl-amino)]-6-methyl-nicotinic acid methyl ester
Embodiment 202
4-(1-ethyl-propyl group amino)-2-(4-methoxyl group-2,6-dimethoxy-phenoxy group)-6-methyl-nicotinic acid methyl ester
APCI?M＝！[387.3].1H?NMR(CDCl 3)
Embodiment 203
2-(2,6-dimethyl-4-[1,3,4] oxadiazole-2-base-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.43(s，1H)，8.22(br?d，1/2H)，7.80(s，2H)，6.12(s，1H)，3.88(s，3H)，3.3-3.4(m，1H)，2.15-2.2(m，9H)，1.5-1.7(m，4H)，0.967(t，6H，J＝7Hz)
13C?NMR(CDCl 3)d.
APCI+m/z＝425.3(M+1)
Embodiment 204
2-(4-chloro-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.14(d，1H，J＝8Hz)，6.90-7.26(m，3H)，6.14(s，1H)，3.82(s，3H)，3.77(s，3H)，3.32-3.73(m，1H)，2.17(s，3H)，1.49-1.67(m，4H)，0.94(t，6H，J＝7Hz)ppm.
Embodiment 205
4-(1-methylol-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1HNMR(CDCl 3)8.21(d，1H)，6.60(s，2H)，6.30(s，1H)，3.87(s，3H)，3.78(s，3H)，3.65(m，3H)，2.17(s，3H0，2.09(s，6H)，1.75(m，1H)，1.61(m，1H)，1.01(t，3H)ppm
Embodiment 206
2-(4-chloro-2-fluoro-6-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
APCI+m/z＝411(M+1)，413(M+3)
Embodiment 207
2-(4-chloro-2-methoxyl group-6-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.16-8.20(m，1H)，6.82(d，1H，?J＝1.5Hz)，6.78(d，1H，J＝1.5Hz)，6.09(s，1H)，3.85(s，3H)，3.72(s，3H)，3.3-3.8(m，1H)，2.12(s，3H)，1.51-1.67(m，4H)，0.95(t，6H，J＝7Hz)ppm.
APCI+m/z＝407.2(M+1)，409.2(M+3)
Embodiment 208
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.2(d，1H)，7.02(s，2H)，6.14(s，1H)，3.87(s，3H)，3.6(m，1H)，3.56(m，1H)，3.4(m，1H)，3.39(s，3H)，2.10(s，3H)，2.07(s，6H)，1.78(m，1H)，1.61(m，1H)，1.00(t，3H)ppm.
Embodiment 209
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.14(br?d，1H)，7.03-7.07(m，2H)，6.88(d，1H，J＝8Hz)，6.14(s，1H)，3.82(s，3H)，3.77(s，3H)，3.32-3.37(m，1H)，2.18(s，3H)，1.49-1.68(m，4H)，0.94(t，6H，J＝7Hz)APCI+m/z＝437.1(M+1)，439.1(M+3)
Embodiment 210
2-(4-chloro-2-hydroxyl-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
In methylene dichloride, at room temperature, by with 2-(4-chloro-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester and BBr 3Reaction, up to all starting raw material consumption, the preparation title compound.The standard treatment step obtains title compound.APCI+m/z＝379.2(M+1)，381.2(M+3)
Embodiment 211
2-(4-chloro-2-oxyethyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.10(br?d，1H)，6.98(d，1H，J＝8Hz)，6.86-6.91(m，2H)，6.14(s，1H)，3.97(q，2H，J＝7Hz)，3.83(s，3H)，3.32-3.37(m，1H)，2.16(s，3H)，1.50-1.68(m，4H)，1.19(t，3H，J＝7Hz)，0.94(t，6H，J＝7Hz)ppm.APCI+m/z＝407.1(M+1)，409.1(M+3)
Embodiment 212
4-(2-hydroxyl-1-methylol-ethylamino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1HNMR(CDCl 3)8.42(d，1H)，7.02(s，2H)，6.17(s，1H)，3.89(m，2H)，3.86(s，3H)，3.85(m，2H)，3.67(m，1H)，2.10(s，3H)，2.05(s，6H)ppm
Embodiment 213
4-(1-carboxyl-propyl group amino)-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
At room temperature, with 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-formyl radical-propyl group amino)-6-methyl-nicotinic acid methyl ester, 2-methyl-2-butene, excessive NaClO 2And NaH 2PO 4Mixture stir 15min.Mixture is adopted the saturated sodium bicarbonate quenching and adopts hexane extraction.Water layer is acidified to pH4 and adopts extracted with diethyl ether twice.Organic layer is separated the dry and concentrated title compound that obtains.Roughage by silica gel chromatography, is obtained the required product into white crystal after recrystallization.Ultimate analysis C 20H 23N 2O 5The Cl calculated value, C, 59.04; H, 5.70; N, 6.89; Measured value C, 59.29; H, 5.73; N, 6.83.
Embodiment 214
4-(1-carboxyl-propyl group amino)-2-(4-chloro-2,6-dimethyl-phenoxy group)-5-chloro-6-methyl-nicotinic acid methyl ester
Prepare title compound by the method in embodiment 213, difference is to be used in to stir under the situation that does not have the 2-methyl-2-butene to spend the night and replaces 15 minute reaction times.
Embodiment 215
4-(1-formamyl-propyl group amino)-5-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
Mixture in methylene dichloride stirs 15min with 4-(1-carboxyl-propyl group amino)-2-(4-chloro-2,6-dimethyl-phenoxy group)-5-chloro-6-methyl-nicotinic acid methyl ester and excessive thionyl chloride.Mixture is concentrated to drying.Resistates is adopted methylene dichloride dilution and ammonia (ammonium) bubbling is joined in the reaction mixture.After stirring 30min, mixture is adopted the water quenching, adopt dichloromethane extraction.Organic layer is concentrated to drying.Resistates is obtained title compound by silica gel Biotage purifying.
1HNMR(CDCl 3)7.02(s，2H)，6.34(s，1H)，5.92(d，1H)，5.81(s，1H)，4.05(m，1H)，3.92(s，3H)，2.27(s，3H)，2.05(s，6H)，1.80(m，2H)，1.00(t，3H)ppm
By similar in appearance to aforesaid method, in methylene dichloride, adopt carboxylic acid and excessive thionyl chloride to begin, concentrate, adopt ammonium, alkylamine, dialkylamine or alkanol (as methyl alcohol, ethanol etc.) quenching, be prepared as follows compound (embodiment 216-223):
Embodiment 216
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxycarbonyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1HNMR(CDCl 3)8.52(d，1H)，7.02(s，2H)，5.97(s，1H)，4.09(m，1H)，3.89(s，3H)，3.78(s，3H)，2.09(s，3H)，2.06(s，6H)，1.98(m，2H)，1.04(t，3H)ppm
Embodiment 217
4-(1-formamyl-propyl group amino)-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.56(d，1H)，7.04(s，2H)，6.38(s，1H)，6.12(s，1H)，5.44(s，1H)，3.91(s，3H)，3.88(m，1H)，2.15(s，1H)，2.07(s，1H)，1.95(m，2H)，1.24(t，3H)ppm
Embodiment 218
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-methoxyl group formamyl-propyl group amino)-nicotinic acid methyl ester
1HNMR(CDCl 3)8.49(d，1H)，7.05(s，2H)，6.48(s，1H)，6.08(s，1H)，3.91(s，3H)，3.90(m，1H)，2.83(m，3H)，2.15(s，3H)，2.08(m，6H)，1.08(t，3H)ppm
Embodiment 219
5-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-methoxyl group formamyl-propyl group amino)-nicotinic acid methyl ester
1HNMR(CDCl 3)7.02(s，2H)，6.42(m，1H)，5.80(m，1H)，3.96(m，1H)，3.89(s，3H)，2.86(d，3H)，2.28(s，3H)，2.04(m，6H)，1.78(m，2H)，0.98(t，3H)ppm
Embodiment 220
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-formyl-dimethylamino-propyl group amino)-6-methyl-nicotinic acid methyl ester
1HNMR(CDCl 3)8.67(d，1H)，7.02(s，2H)，5.97(s，1H)，4.39(m，1H)，3.89(s，3H)，3.13(s，3H)，3.02(s，3H)，2.13(s，3H)，2.06(m，6H)，1.92(m，2H)，1.00(t，3H)ppm
Embodiment 221
5-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-formyl-dimethylamino-propyl group amino)-6-methyl-nicotinic acid methyl ester
1HNMR(CDCl 3)7.02(s，2H)，6.42(d，1H)，4.66(m，1H)，3.93(s，3H)，3.06(s，3H)，3.01(s，3H)，2.27(s，3H)，1.82(m，2H)，0.90(t，3H)ppm
Embodiment 222
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-[(1-(tetramethyleneimine-1-carbonyl)-propyl group amino]-nicotinic acid methyl ester
1HNMR(CDCl 3)8.61(d，1H)，7.02(s，2H)，5.97(s，1H)，4.20(m，1H)，3.89(s，3H)，3.59(m，4H)，2.13(s，3H)，2.01(m，12H)，1.02(t，3H)ppm
Embodiment 223
5-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-[(1-(tetramethyleneimine-1-carbonyl)-propyl group amino]-nicotinic acid methyl ester
1HNMR(CDCl 3)7.02(s，2H)，6.41(d，1H)，4.44(m，1H)，3.93(s，3H)，3.56(m，2H)，3.47(m，2H)，2.26(s，3H)，2.06(s，6H)，2.00(m，6H)，0.91(t，3H)ppm
Embodiment 224
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-methylamino methyl-propyl group amino)-nicotinic acid methyl ester
(67mg, 0.17mmol) mixture in ethylene dichloride (2ml) is with methylamine, 1 acetate, anhydrous Na with 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-formyl radical-propyl group amino)-6-methyl-nicotinic acid methyl ester 2SO 4Handle with anhydrous sodium cyanoborohydride, and at room temperature stir and spend the night.The quenching of mixture water, dichloromethane extraction separates organic layer, drying concentrates, and use methylene dichloride to 5% methyl alcohol in methylene dichloride as eluent, by silica gel Biotage purifying, obtain title compound into pale solid.1HNMR(CDCl 3)8.07(d，1H)，7.02(s，2H)，6.29(s，1H)，3.87(s，3H)，3.80(m，1H)，2.88(m，2H)，2.56(s，3H)，2.11(s，3H)，2.06(s，6H)，1.63(m，2H)，0.99(t，3H)ppm
With to the similar reduction amination method of in embodiment 224, describing, be prepared as follows compound (embodiment 225-227).
Embodiment 225
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-tetramethyleneimine-1-ylmethyl-propyl group amino)-nicotinic acid methyl ester
1HNMR(CDCl 3)8.11(d，1H)，6.99(s，2H)，6.12(s，1H)，3.84(s，3H)，3.54(m，1H)，3.43(m，2H)，2.56(m，4H)，2.07(s，3H)，2.06(s，6H)，1.84(m，6H)，.96(t，3H)ppm
Embodiment 226
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-cyclopropyl amino methyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.07(d，1H)，7.02(s，2H)，6.31(s，1H)，3.87(s，3H)，3.79(m，1H)，2.96(m，1H)，2.36(m，1H)，2.11(s，3H)，2.07(s，6H)，1.83(m，1H)，1.61(m，1H)，0.99(t，3H)，0.98(m，4H)ppm
Embodiment 227
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-{1-[(cyclopropyl methyl-amino)-methyl]-propyl group amino }-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.07(d，1H)，7.02(s，2H)，6.55(s，1H)，4.12(m，1H)，3.88(s，3H)，3.06(d，2H)，2.87(m，2H)，2.16(s，3H)，2.05(s，6H)，2.03(m，1H)，1.69(m，1H)1.25(m，1H)1.03(t，3H)，0.66(m，2H)，0.38(m，2H)ppm
Embodiment 228
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethylamino methyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
Adopt sodium iodide, ethamine and triethylamine to handle the solution of 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-mesyloxy methyl-propyl group amino)-6-methyl-nicotinic acid methyl ester in acetonitrile.The mixture heating up to 70 that obtains ℃ is spent the night,, spend the night in 100 ℃ then, show no starting raw material up to thin-layer chromatography then at 85 ℃ of following 6hrs.The mixture that obtains is adopted the water quenching and adopts ethyl acetate extraction.Organic layer is separated, and drying concentrates, and purifying obtains the title compound into oil.1HNMR(CDCl 3)d?8.06(d，1H)，7.02(s，2H)，6.31(s，1H)，3.88(s，3H)，3.86(m，1H)，2.85(m，4H)，2.12(s，3H)，2.07(s，6H)，1.64(m，1H)，1.60(m，1H)，1.27(m，3H)，.99(t，3H)
Embodiment 229
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-{1-[(ethyl-methyl-amino)-methyl]-propyl group amino }-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.18(d，1H)，7.02(s，2H)，6.19(m，1H)，3.86(s，3H)，3.56(m，3H)，3.37(m，2H)，2.11(s，3H)，2.07(s，6H)，1.80(m，1H)，1.60(m，2H)，1.25(m，4H)，0.97(t，3H)ppm
Embodiment 230
4-(1-butyl amino methyl-propyl group amino)-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.07(d，1H)7.02(s，1H)，6.25(s，1H)，3.87(s，3H)，3.79(m，1H)，2.79(m，2H)，2.69(m，2H)，2.10(s，3H)，2.07(s，6H)，1.75(m，2H)，1.57(m，4H)，1.00(t，3H)，0.92(t，6H)ppm
Embodiment 231
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-{1-[(cyclopropyl methyl-propyl group-amino)-methyl]-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.01(d，1H)，7.02(s，2H)，6.13(s，1H)，3.85(s，3H)，3.48(m，1H)，2.58(m，2H)，2.37(m，1H)，2.09(s，3H)，2.07(s，6H)，1.82(m，1H)1.42(m，2H)，1.25(m?4H)，0.97(t，t，3H)，0.86(m，6H)ppm
Embodiment 232
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-propyl group amino methyl-propyl group amino)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.09(d，1H)，7.02(s，2H)，6.19(s，1H)，3.86(s，3H)，3.60(m，1H)，2.76(m，2H)，2.61(t，2H)，2.10(s，3H)，2.07(s，6H)，1.61(m，6H)，0.97(t，3H)，0.91(t，3H)ppm
Embodiment 233
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-{[(furans-2-ylmethyl)-amino]-methyl }-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.09(d，1H)，7.37(s，1H)，7.02(s，2H)，6.31(dd，2H)，6.17(s，1H)，3.87(s，3H)，3.84(s，2H)，3.58(m，1H)，2.75(m，2H)，2.09(s，3H)，2.07(s，6H)，1.70(m，1H)，1.58(m，1H)，0.95(t，3H)ppm
Embodiment 234
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-{1-[(2-methoxyl group-ethylamino)-methyl]-propyl group amino }-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.10(d，1H)，7.02(s，2H)，6.19(s，1H)，3.87(s，3H)，3.61(m，1H)，3.51(m.2H)，3.34(s，3H)，2.84(m，2H)，2.79(m，2H)，2.10(s，3H)，2.07(s，6H)，1.71(m，1H)，1.57(m，1H)，0.98(t，3H)ppm
Embodiment 235
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-dimethylaminomethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1HNMR(CDCl 3)8.14(d，1H)，7.02(s，2H)，6.10(s，1H)，3.86(s，3H)，3.53(m，1H)，2.44(m，2H)，2.29(s，6H)，2.10(s，3H)，2.07(s，6H)，1.78(m，1H)，1.56(m，1H)，0.97(t，3H)ppm
Embodiment 236
4-[(2-butyl amino-ethyl)-ethyl-amino]-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1HNMR(CDCl 3)7.00(s，2H)，6.31(s，1H)，3.88(s，3H)，3.41(t，2H)，3.26(m，2H)，2.82(t，2H)，2.65(t，2H)，2.15(s，3H)，2.05(s，6H)，1.51(m，2H)，1.34(m，2H)，1.12(t，3H)，0.89(t，3H)ppm
Embodiment 237
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S, S)-(1-ethyl-2-methylamino-propyl group amino)-6-methyl-nicotinic acid methyl ester
By reduction amination as implied above, adopt 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-oxo-propyl group amino)-6-methyl-nicotinic acid methyl ester and methylamine to begin, the preparation title compound.
APCI?M+1[420.2].1H?NMR(CDCl 3)
Embodiment 238
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S, R)-(1-ethyl-2-methylamino-propyl group amino)-6-methyl-nicotinic acid methyl ester
By reduction amination as implied above, adopt 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-oxo-propyl group amino)-6-methyl-nicotinic acid methyl ester and methylamine to begin, the preparation title compound.
APCI?M+1[420.2]，1H?NMR(CDCl 3)
Embodiment 239
2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-methyl sulfenyl methyl-propyl group amino)-nicotinic acid methyl ester
At room temperature, the mixture in acetonitrile stirs 2hr with 2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-4-(1-mesyloxy methyl-propyl group amino)-6-methyl-nicotinic acid methyl ester and sodium iodide, adds NaSMe then.With mixture 60 ℃ of following heated overnight.Add DMSO and other NaSMe and heat other a few hours and run out of up to all starting raw materials.Mixture is adopted the water quenching, adopt ethyl acetate extraction.Organic layer is separated, and drying concentrates, and purifying obtains title compound.
1HNMR(CDCl 3)8.23(d，1H)，6.59(s，2H)，6.10(s，1H)，3.87(s，3H)，3.78(s，3H)，3.60(m，1H)，2.75(m，1H)，2.65(m，1H)，2.14(s，3H)，2.08(m，9H)，1.85(m，1H)，1.66(m，1H)，1.00(t，3H)ppm
Method by describing in embodiment 239 adopts suitable 2-(substituent phenoxy)-4-(1-mesyloxy methyl-propyl group amino)-3, and 6-substituted pyridines and suitable nucleophilic reagent are prepared as follows compound (embodiment 240-243):
Embodiment 240
2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-[1,2,4] triazol-1-yl methyl-propyl group amino)-nicotinic acid methyl ester
1H(CDCl 3)8.23(d，1H)，8.02(s，1H)，7.95(s，2H)，5.92(s，1H)，6.59(s，2H)，5.93(s，1H)，4.31(m，1H)，4.22(m，1H)，3.93(m，1H)，3.87(s，3H)，3.77(s，3H)，2.10(s，3H)，2.07(s，6H)，1.70(m，1H)，1.59(m，1H)，1.04(t，3H)ppm
Embodiment 241
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-methyl sulfenyl methyl-propyl group amino)-nicotinic acid methyl ester
1HNMR(CDCl 3)8.27(d，1H)，7.02(s，2H)，6.12(s，1H)，3.87(s，3H)，3.61(m，1H)，2.70(m，2H)，2.17(s，3H)，2.14(s，3H)，2.08(s，6H)，1.85(m，2H)，1.00(t，3H)ppm
Embodiment 242
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(2-ethyl-aziridine-1-yl)-6-methyl-nicotinic acid methyl ester
7.02(s，2H)，6.38(s，1H)，3.95(s，3H)，2.27(m，1H)，2.18(s，3H)，2.15(m，2H)，2.06(s，6H)，1.75(m，1H)，1.63(m，1H)，1.06(t，3H)ppm.
Embodiment 243
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-[1-(3H-[1,2,3] triazole-4-base sulfenyl methyl)-propyl group amino]-nicotinic acid methyl ester
1HNMR(CDCl 3)8.32(d，1H)，7.54(s，1H)，6.95(s，2H)，6.13(s，1H)，3.87(s，3H)，3.67(m，1H)，3.20(m，1H)，3.05(m，1H)，2.05(m，9H)，1.99(m，1H)，1.67(m，1H)，1.01(t，3H)ppm
Embodiment 244
2-(4-chloro-2,6-two. methyl-phenoxy group)-4-(1-methylol-3-methylsulfonyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
In methylene dichloride, at room temperature, adopt metachloroperbenzoic acid that 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-3-methyl sulfenyl-propyl group amino)-6-methyl-nicotinic acid methyl ester is carried out oxidation 2hrs, the preparation title compound.1H?NMR(CDCl 3)d?8.32(d，1H)，7.04(s，2H)，6.23(s，1H)，3.88(s，3H)，3.7-3.9(m，3H)，3.1-3.3(m，2H)，2.95(s，3H)，2.0-2.4(m，2H)，2.13(s，3H)，2.07(s，6H)ppm.
Method by describing in embodiment 188 is prepared as follows compound (embodiment 245-248).
Embodiment 245
2-(4-oxyethyl group-2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.35(d，1H)，6.59(s，2H)，6.08(s，1H)，4.03(m，1H)，4.01(m，4H)，3.99(m，1H)，3.92(s，3H)，3.89(m，1H)，2.34(m，1H)，2.25(m，3H)，2.08(s，6H)，1.39(t，3H)ppm
Embodiment 246
2-[4-(2-methoxyl group-oxyethyl group)-2,6-dimethyl-phenoxy group]-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.30(d，1H)，6.62(s，2H)，6.07(s，1H)，4.10(m，3H)，4.02(m，2H)，3.98(m，1H)，3.85(s，2H)，3.75(m，3H)，3.45(s，3H)，2.32(m，1H)，2.19(s，3H)，2.07(s，6H)ppm
Embodiment 247
2-(2,6-dimethyl-4-trifluoromethoxy-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.29(d，1H，J＝6Hz)，6.91(s，2H)，6.06(s，1H)，4.11-4.33(m，1H)，3.97-4.05(m，2H)，3.89-3.93(m，1H)，3.87(s，3H)，3.72-3.76(m，1H)，2.31-2.35(m，1H)，2.14(s，3H)，2.10(s.6H)，1.94-1.96(m，1H)ppm.APCI+m/z＝441.2(M+1)
Embodiment 248
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(R)-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester
APCI+m/z＝391.3(M+1)
Embodiment 249
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-3-iodo-propyl group amino)-6-methyl-nicotinic acid methyl ester
APCI[M+1]518.9，520.9
Embodiment 250
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-3-methanesulfinyl-propyl group amino)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.31(d，1H)，7.03(s，2H)，6.24(s，0.5H)，6.28(s，0.5H)，3.87(s，3H)，3.65-3.9(m，3H)，2.7-3.0(m，2H)，2.60(s，3H)，2.0-2.4(m，2H)，2.14(s，3H)，2.07(s，6H)ppm.
Embodiment 251
2-(4-encircles propoxy--2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?8.32(d，1H)，6.73(s，2H)，6.07(s，1H)，4.13(m，1H)，4.01(m，4H)，3.98(m，1H)，3.85(s，3H)，3.72(m，2H)，2.22(s，3H)，2.09(s，6H0，.87(m，2H)，.75(m，4H)ppm
Embodiment 252
2-(4-chloro-2,6-dimethoxy-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester
Embodiment 253
4-sec-butyl amino-6-methyl-2-(2,4,6-trimethylammonium-pyridin-3-yl oxygen)-nicotinic acid methyl ester;
1H?NMR(CDCl 3)8.08(d，1H)，686(s，1H)，6.09(s，1H)，3.86(s，3H)，3.48(m，1H)，2.49(s，3H)，2.31(s，3H)，2.08(s，6H)，1.63(m，2H)，1.21(d，3H)，0.98(t，3H)ppm
Embodiment 254
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-{ ethyl-[2-(ethyl-methyl-amino)-ethyl]-amino }-6-methyl-nicotinic acid methyl ester
Embodiment 255
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-[ethyl-(2-propyl group amino-ethyl)-amino]-6-methyl-nicotinic acid methyl ester
Embodiment 256
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-pyridin-3-yl oxygen)-nicotinic acid methyl ester;
1H?NMR(CDCl 3)8.09(d，1H)，6.86(s，1H)，6.08(s，1H)，3.86(s，3H)，3.33(m，1H)，2.49(s，3H)，2.31(s，3H)，2.07(s，6H)，1.63(m，4H)，0.94(t，6H)ppm
1H?NMR(CDCl 3)d?8.39?d，1H，J＝6Hz)，6.63(s，2H)，6.06(s，1H)，4.08-4.15(m，1H)，3.95-4.05(m，2H)，3.88-3.92(m，1H)，3.86(s，3H)，3.73(s，6H)，3.67-3.73(m，1H)，2.26-2.35(m，1H)，2.14(s，3H)，1.89-1.96(m，1H)ppm.
Following embodiment 257-287 relates to other compound of general formula I of the present invention, wherein R 4Be-C (O) NR 24R 25:
By the method in embodiment 113, begin and adopt suitable nucleophilic reagent quenching from corresponding nicotinic acid or pyrimidine-5-carboxylic acid's derivative, be prepared as follows compound (embodiment 257-280); Also can be in NMP, under 130-160 ℃, by 2-(substituent phenoxy)-6-methyl-4-chloro-niacinamide and/or-N-replaces the coupling of niacinamide, prepares these compounds:
Embodiment 257
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-niacinamide
1H?NMR(CDCl 3)d?9.99(d，1H)，7.85(brs，1H)，7.07(s，2H)，6.13(s，1H)，5.62(brs，1H)，3.7-4.2(m，5H)，2.95(d，3H)，2.31(m，1H)，2.20(s，3H)，2.09(s，6H)，2.01(m，1H)ppm.
Embodiment 258
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-3-methyl sulfenyl-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.78(d，1H)，7.97(brs，1H)，7.06(s，2H)，6.32(s，1H)，5.77(brs，1H)，3.6-3.9(m，3H)，2.5-2.7(m，2H)，2.0-2.2(m，12H)，1.8-2.0(m，2H)ppm.
Embodiment 259
2-(4-chloro-2,6-dimethyl-phenoxy group)-6, N-dimethyl-4-(S)-(tetrahydrochysene-furans-3-base is amino)-niacinamide
1H?NMR(CDCl 3)d?10.00(d，1H)，8.05(brs，1H)，7.06(s，2H)，6.10(s，1H)，4.09(m，1H)，3.96-4.05(m，3H)，3.73(m，1H)，2.95(d，3H)，2.31(m，1H)，2.12(s，3H)，2.06(s，6H)，1.96(m，1H)ppm.
Embodiment 260
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-propyl group amino)-6, N-dimethyl-niacinamide
1H?NMR(CDCl 3)d?9.78(d，1H)，8.10(brs，1H)，7.06(s，2H)，6.13(s，1H)，3.32(m，1H)，2.96(d，3H)，2.09(s，3H)，2.08(s，6H)，1.65(m，4H)，0.96(t，6H)ppm.
Embodiment 261
4-sec-butyl amino-2-(4-chloro-2,6-dimethyl-phenoxy group)-6, N-dimethyl-niacinamide
1H?NMR(CDCl 3)d?9.78(d，1H)，8.04(brs，1H)，7.07(s，2H)，6.14(s，1H)，3.46(m，1H)，2.95(d，3H)，2.15(s，3H)，2.09(s，6H)，1.1.58(m，2H)，1.23(d，3H)，0.99(t，6H)ppm.
Embodiment 262
4-(1-ethyl-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-niacinamide
Mp=184 ℃ of measured value: C, 67.68, H, 8.12, N, 10.81; Calculated value: C, 67.90, H, 7.87, N, 11.31.
1H(CDCl 3)9.67(d，1H)，8.06(m，1H)6.61(s，2H)，6.11(s，1H)，5.48(s，1H)，3.79(s，3H)，3.32(m，
1H)，2.09(s，9H)，1.61(s，4H)，0.95(t，6H)ppm
Embodiment 263
4-(1-ethyl-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6, N-dimethyl-niacinamide
1H(CDCl 3)9.78(d，1H)，8.22(m，1H)，6.60(s，2H)，6.10(s，1H)，3.78(s，3H)，3.25(m，1H)，2.93(d，3H)，2.07(s，9H)，1.61(m，4H)，0.95(t.6H)ppm
Embodiment 264
2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6-methyl-niacinamide
1HNMR(CDCl 3)9.80(d，1H)，8.04(s，1H)，6.61(s，2H)，6.18(s，1H)，5.62(s，1H)，3.78(s，3H)，3.51(m，2H)，3.39(s，3H)，2.09(s，3H)，2.08(s，6H)，1.79(m，1H)，1.59(m，1H)，0.99(t，3H)ppm
Embodiment 265
2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6, N-dimethyl-niacinamide
1HNMR(CDCl 3)9.92(d，1H)，8.22(s，1H)，6.62(s，2H)，6.19(s，1H)，3.79(s，3H)，3.5(m，2H)，3.38(s，3H)，2.94(d，3H)，2.12(s，3H)，2.08(s，6H)，1.80(m，1H)，1.61(m，1H)，1.00(t，3H)ppm
Embodiment 266
4-(1-methylol-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6, N-dimethyl-niacinamide
1HNMR(CDCl 3)9.79(d，1H)，8.28(d，1H)，6.62(s，2H)，6.24(s，1H)，3.79(s，3H)，3.70(m，2H)，3.54(m，1H)，2.94(d，3H)，2.08(s，6H)，1.62(m，2H)，1.01(t，3H)ppm
Embodiment 267
4-sec-butyl amino-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6, N-dimethyl-niacinamide
1HNMR(CDCl 3)9.76(d，1H)，8.26(d，1H)，6.61(s，2H)，6.12(s，1H)，3.79(s，3H)，3.46(m，1H)，2.94(d，3H)，2.09(s，3H)，2.07(s，6H)，1.64(m，2H)，1.24(m，3H)，0.98(t，3H)ppm
Embodiment 268
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-methoxymethyl-propyl group amino)-6, N-dimethyl-niacinamide
Ultimate analysis C 21H 28ClN 3O 3Calculated value C, 62.14%H, 6.95%, N, 10.35%; Measured value C, 62.12%, H, 6.95%, N, 10.42%.
Embodiment 269
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(S)-(1-methoxymethyl-propyl group amino)-6-methyl-niacinamide
Ultimate analysis C 20H 26ClN 3O 3Calculated value C, 61.30%H, 6.69%, N, 10.725%; Measured value C, 60.97%, H, 6.53%, N, 10.47%.
Embodiment 270
2-(4-chloro-2,6-dimethyl-phenoxy group)-6, N-dimethyl-4-(1-methyl sulfenyl methyl-propyl group amino)-niacinamide
1HNMR(CDCl 3)9.97(d，1H)，8.1(brs，1H)，7.06(s，2H)，6.16(s，1H)，3.56(m，1H)，2.96(s，3H)，2.6-2.8(m，2H)，2.17(s，3H)，2.11(s，3H)，2.08(s，6H)，1.6-1.9(m，2H)，1.24(m，3H)，1.00(t，3H)ppm
Embodiment 271
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-methyl sulfenyl methyl-propyl group amino)-niacinamide
1HNMR(CDCl 3)9.89(d，1H)，7.9(brs，1H)，7.06(s，2H)，6.16(s，1H)，3.56(m，1H)，2.6-2.8(m，2H)，2.17(s，3H)，2.11(s，3H)，2.07(s，6H)，1.6-1.9(m，2H)，1.24(m，3H)，0.99(t，3H)ppm
Embodiment 272
2-(4-chloro-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6, N-dimethyl-niacinamide
1H?NMR(CDCl 3)d?9.40(d，1H，J+8Hz)，8.10(br?s，1H)，7.17(d，1H，J＝9Hz)，6.94-6.96(m，2H)，6.14(s，1H)，3.79(s，3H)，3.27-3.31(m，1H)，2.93(d，J＝5Hz)2.14(s，3H)，1.51-1.66(m，4H)，0.95(t，6H，J＝7Hz)ppm..CI+m/z＝392.2(M+1)，394.2(M+3)
Embodiment 273
2-(4-chloro-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.40(d，1H)，7.92(brs，1H)，7.17(d，1H，J＝9Hz)，6.94-6.96(m，2H)，6.15(s，1H)，5.48(br?s，1H)，3.77(s，3H)，3.28-3.36(m，1H)，2.16(s，3H)，1.52-1.66(m，4H)，0.94(t，6H，J＝7Hz)ppm.APCI+m/z＝378.1(M+1)，380.1(M+3)
Embodiment 274
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-cyclo propyl methoxy methyl-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.70(d，1H)，7.90(brs，1H)，7.05(s，1H)，6.22(s，1H)，5.6(br?s，1H)，3.57(m，2H)，3.43(m，1H)，3.33(d，3H)，2.09(s，6H)，2.07(s，3H)，1.5-1.9(m，2H)，0.9-1.0(m，4H)，0.53(m，2H)，0.50(m，2H)ppm.
Embodiment 275
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethoxyl methyl-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.75(d，1H)，7.90(brs，1H)，7.05(s，1H)，6.21(s，1H)，5.6(br?s，1H)，3.3-3.6(m，4H)，2.08(s，6H)，2.07(s，3H)，1.5-1.9(m，2H)，1.20(t，3H)，1.00(t，3H)ppm.
Embodiment 276
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethoxyl methyl-propyl group amino)-N-ethyl-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.78(d，1H)，8.09(t，1H)，7.06(s，1H)，6.22(s，1H)，5.6(br?s，1H)，3.3-3.6(m，6H)，2.09(s，3H)，2.08(s，6H)，1.5-1.9(m，2H)，1.20-1.4(m，6H)，1.00(t，3H)ppm.
Embodiment 277
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethoxyl methyl-propyl group amino)-6, N-. dimethyl-niacinamide
1H?NMR(CDCl 3)d?9.8(d，1H)，8.1(brs，1H)，7.06(s，1H)，6.22(s，1H)，3.54(m，3H)，3.38(m，1H)，2.94(d，3H)，2.08(s，6H)，2.07(s，3H)，1.83(m，1H)，1.60(m，1H)，1.20(t，3H)，1.00(t，3H)ppm.
Embodiment 278
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6, N-dimethyl-niacinamide
1H?NMR(CDCl 3)d?9.41(br?d，1H)，8.08(br?s，1H)，7.09-7.12(m，3H)，6.15(s，1H)，3.79(s，1H)，3.28-3.33(m，1H)，2.93(d，3H，J＝5Hz)，2.15(s，3H)，1.501-1.65(m，4H)，0.95(t，6H，J＝8Hz)APCI+m/z＝436.1(M+1)，438.1(M+3)
Embodiment 279
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.39(br?d，1H)，7.91(br?s，1H)，7.09-7.11(m，3H)，6.15(s，1H)，5.49(br?s，1H)，3.77(s，3H)，3.29-3.34(m，1H)，2.15(s，3H)，1.51-1.67(m，4H)，0.94(t，6H，J＝7Hz)ppm.APCI+m/z＝422.1(M+1)，424.1(M+3)
Embodiment 280
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-chloromethyl-propyl group amino)-6-methyl-niacinamide
1H?NMR(CDCl 3)d?9.93(d，1H)，7.9(brs，1H)，7.06(s，2H)，6.16(s，1H)，5.6(brs，1H)，3.4-3.7(m，3H)，2.1(s，3H)，2.08(s，6H)，1.9(m，1H)，1.65(m，1H)，1.03(t，3H)ppm.
Embodiment 281
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-formyl radical-propyl group amino)-6-methyl-niacinamide
At room temperature, the mixture in methylene dichloride/DMSO stirs 4hr with 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-niacinamide and Dess-Martin reagent.After standard processing and silica gel Biotage purifying, separate title compound.
1H?NMR(CDCl 3)d?9.52(s，1H)，8.00(brs，1H)，7.06(s，22H)，5.99(s，1H)，5.8(brs，1H)，3.85(m，1H)，2.09(s，3H)，2.08(s，6H)，1.8-2.2(m，2H)，1.08(t，3H)ppm.
Embodiment 282
4-(1-formyl radical-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6, N-dimethyl-niacinamide
By similar in appearance to the method for in embodiment 281, describing, prepare title compound.
1HNMR(CDCl 3)9.51(s，1H)，8.32(m，1H)，6.62(s，2H)，5.97(s，1H)，3.81(m，1H)，3.79(s，3H)，2.96(m，3H)，2.08(m，9H)，1.89(m，2H)，1.09(t，3H)ppm
Embodiment 283
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-hydroxyl-propyl group amino)-6-methyl-niacinamide
Under-78 ℃, in the MeMgBr solution in dry THF, be added in 2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-formyl radical-propyl group the amino)-6-methyl-nicotinamide soln in the dry THF.Mixture is stirred 2hr down at-78 ℃, adopt the diluted acid quenching then.After standard extraction and purifying, obtain title compound.1H?NMR(CDCl 3)d?9.8(d，1H)，7.9(nbrs，1H)，7.05(s，2H)，6.27(s，0.5H)，6.24(s，0.5H)，5.6(brs，1H)，3.91(m，0.5H)，3.89(m，0.5H)，3.51(m，0.5H)，3.3(m，0.5H)，2.09(s，9H)，1.5-1.8(m，2H)，1.26(d，3H)，0.98(t，3H)ppm.
Embodiment 284
4-(1-ethyl-2-methoxyl group-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6, N-dimethyl-niacinamide
1HNMR(CDCl 3)9.87(d，1H)，8.26(d，1H)，6.61(s，2H)，6.16(s，1H)，3.79(s，3H)，3.46(m，1H)，3.40(s，3H)，2.94(d，3H)，2.08(s，9H)，1.76(m，1H)，1.65(m，1H)，1.25(m，1H)，1.17(d，3H)，0.98(t，3H)ppm?mp＝122.6℃
Embodiment 285
2-(4-bromo-2,6-dimethyl-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide
To 2-chloro-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide and 2,6-dimethyl-4-bromo-phenol adds t-BuOK in the mixture of NMP.With the mixture heated overnight in 160 ℃ of oil baths that obtains.Mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer is separated, dry and concentrated, by silica gel Biotage purifying, obtain title compound then.
1H?NMR(CDCl 3)d?9.69(d，1H)，7.89(brs，1H)，7.20(s，2H)，6.13(s，1H)，5.5(brs，1H)，3.3(m，1H)，2.10(s，3H)，2.09(s，6H)，1.6(m，4H)，0.95(t，6H)ppm.
Embodiment 286
4-(1-ethyl-2-methoxyl group-propyl group amino)-6, N-dimethyl-2-(2,4,6-trimethylammonium-pyridin-3-yl oxygen)-niacinamide
1H(CDCl 3)9.74(d，1H)，8.08(s，1H)，6.90(s，1H)，6.12(s，1H)，3.31(m，1H)，2.96(d，3H)，2.51(s，3H)，2.30(s，3H)，2.08(s，3H)，2.05(s，3H)，1.60(m，4H)，0.95(t，3H)ppm
Embodiment 287
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-pyridin-3-yl oxygen)-niacinamide
MP＝164.3℃?1H?NMR(CDCl 3)9.65(d，1H)，7.8(s，1H)，6.91(s，1H)，6.14(s，1H)，5.50(s，1H)，3.32(m，1H)，2.53(s，3H)，2.34(s，3H)，2.17(s，3H)，2.10(s，3H)，1.60(m，4H)，0.95(t，6H)ppm
Following embodiment 288-294 relates to other compound of general formula I of the present invention, wherein R 4Be-C (O) R 24, for example-C (O) CH 3:
Embodiment 288
1-[4-(1-ethyl-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-pyridin-3-yl]-ethyl ketone
1HNMR(CDCl 3)9.74(d，1H)，6.61(s，2H)，6.10(s，1H)，3.79(s，3H)，3.39(m，1H)，2.73(s，3H)，2.10(s，9H)，1.62(m，4H)，0.94(t，6H)ppm
Embodiment 289
N-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-(2-tetramethyleneimine-1-base-ethyl)-ethanamide
1H?NMR(CDCl 3)d?6.89(s，2H)，6.60(s，1H)，4.00-4.07(m，1H)，3.53-3.59(m，1H)，2.59-2.72(m，2H)，2.52(br?s，4H)，2.30(s，3H)，2.24(s，3H)，2.22(s，3H)，2.04(s，6H)，1.84(s，3H)，1.74(br?s，4H)ppm.
Embodiment 290
N-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-(2-tetramethyleneimine-1-base-ethyl)-isobutyramide
1H?NMR(CDCl 3)d?6.89(s，2H)，6.56(s，1H)，4.09-4.17(m，1H)，3.38-3.48(m，1H)，2.65-2.77(m，2H)，2.61(br?s，4H)，2.33-2.40(m，1H)，2.30(s，3H)，2.24(s，3H)，2.20(s，3H)，2.05(s，6H)，1.77(br?s，4H)，1.04(t，6H，J＝7Hz)ppm.
Embodiment 291
N-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-(2-tetramethyleneimine-1-base-ethyl)-malonamic acid ethyl ester
1H?NMR(CDCl 3)d?6.89(s，2H)，6.63(s，1H)，4.11-4.17(m，3H)，3.44-3.56(m，1H)，3.15(s，2H)，2.72(br?s，2H)，2.57(br?s，4H)，2.30(s，3H)，2.24(s，3H)，2.23(s，3H)，2.04(s，6H)，1.77(br?s，4H)，1.24(t，3H，J＝7Hz)
Embodiment 292
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-cyclopentyl amino-6-methyl-6-pyridine-3-carbonyl aldehyde
1H?NMR(CDCl 3)d?9.42(d，1H)，7.05(s，2H)，6.09(s，1H)，4.18(brs，1H)，4.06(m，2H)，3.95(m，1H)，3.77(m，1H)，2.35(m，1H)，2.17(s，3H)，2.09(s，6H)，1.98(m，1H)ppm.
Embodiment 293
4-(1-ethyl-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-6-pyridine-3-carbonyl aldehyde
1HNMR(CDCl 3)9.26(d，1H)，6.60(s，2H)，6.10(s，1H)，3.78(s，3H)，3.40(m，1H)，2.14(s，3H)，2.11(s，6H)，1.66(m，4H)，0.96(t，6H)ppm
Embodiment 294
1-[2-(4-chloro-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-pyridin-3-yl]-ethyl ketone
1H?NMR(CDCl 3)d?9.59(br?d，1H)，6.93-7.02(m，3H)，6.14(s，1H)，3.78(s，3H)，3.33-3.38(m，1H)，2.69(s，3H)，2.14(s，3H)，1.49-1.67(m，4H)，0.94(t，6H，J＝7Hz)ppm.
Following embodiment 295-329 relates to other compound of general formula I of the present invention, wherein R 4Be methyl:
Embodiment 295
Sec-butyl-[2-(2,6-dimethyl-4-trifluoromethoxy-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?6.90(s，2H)，6.09(s，1H)，3.78(d，1H，J＝8Hz)，3.45-3.52(m，1H)，2.15(s，3H)，2.10(s，9H)，1.51-1.67(m，2H)，1.23(d，3H，J＝8Hz)，0.98(t，3H，J＝7Hz)ppm.
Embodiment 296
[2-(2,6-dimethyl-4-trifluoromethoxy-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl group)-amine
1H?NMR(CDCl 3)d?6.91(s，2H)，6.08(s，1H)，3.74(d，1H，J＝8Hz)，3.31-3.34(m，1H)，2.15(s，3H)，2.11(s，6H)，2.08(s，3H)，1.49-1.68(m，4H)，.96(t，6H，J＝8Hz)ppm.
Embodiment 297
[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(2-tetramethyleneimine-1-base-ethyl)-(2,2,2-three fluoro-ethyls)-amine
1H?NMR(CDCl 3)d?6.87(s，2H)，6.55(s，1H)，3.78(q，2H，J＝9Hz)，3.60-3.72(m，2H)，2.82-2.98(m，6H)，2.29(s，3H)，2.26(s，3H)，2.20(s，3H)，2.03(s，6H)，1.96(br?s，4H)ppm.
Adopt suitable 2-(substituent phenoxy)-4-(1-mesyloxy methyl-propyl group amino)-3,6-substituted pyridines and suitable amine begin, and are prepared as follows compound (embodiment 298 and 299):
Embodiment 298
N2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-N1-cyclopropyl methyl-butane-1, the 2-diamines
1H?NMR(CDCl 3)d?7.01(s，2H)，6.17(s，1H)，4.40(d，1H)，3.82(m，1H)，3.05(m，2H)，2.69(m，2H)，2.20(s，3H)，2.12(s，3H)，2.04(s，6H)，1.70(m，2H)，.98(t，3H)，.96(m，4H)ppm
Embodiment 299
N-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-ethyl-N ', N '-dimethyl-ethane-1,2-diamines
1H?NMR(CDCl 3)d?6.86(s，2H)，6.43(s，1H)，3.26(AB?quartet，2H)，3.12(q，2H，J＝7Hz)，2.51(AB?quartet，2H)，2.34(s，6H)，2.29(s，3H)，2.23(s，3H)，2.18(s，3H)，2.05(s，6H)，1.09(t，3H，J＝7Hz)ppm.
Embodiment 300
N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-1-methyl-butane-1, the 2-diamines
1HNMR(CDCl 3)6.85(s，2H)，6.12(s，1H)，4012(d，1H)，3.56(m，1H)，2.79(m，2H)，2.47(s，3H)，2.28(s，3H)，2.14(d，6H)，2.06(s，6H)，1.62(m，2H)，0.97(t，3H)ppm
Embodiment 301
N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-1-ethyl-butane-1, the 2-diamines
1H?NMR(CDCl 3)d?7.80(s，1H)，6.85(s，2H)，6.12(s，1H)，4.22(d，1H)，3.57(m，1H)，2.82(m，2H)，2.72(q，2H)，2.28(s，3H)，2.13(s，6H)，2.06(s，6H)，1.63(m，2H)，1.16(t，3H)，0.97(t，3H)ppm
Embodiment 302
N2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N1-ethyl-N1-methyl-butane-1, the 2-diamines
1H?NMR(CDCl 3)d?6.85(s，2H)，6.06(s，1H)，4.58(m，1H)，3.39(m，1H)，2.49(m，4H)，2.28(s，6H)，2.14(s，6H)，2.06(s，6H)，1.66(m，2H)，1.08(m，3H)，0.96(t，3H)ppm
Embodiment 303
N-1-butyl-N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-butane-1, the 2-diamines
1H?NMR(CDCl 3)d?6.85(s，2H)，6.11(s，1H)，4.21(d，1H)，3.51(q，1H)，2.79(m，2H)，2.65(t，2H)，2.28(s，3H)，2.14(s，6H)，2.06(s，6H)，1.62(m，2H)，1.49(m，2H)，1.35(m，2H)，0.97(t，3H)，0.91(t，3H)ppm
Embodiment 304
N-1-cyclopropyl methyl-N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-1-propyl group-butane-1, the 2-diamines
1H?NMR(CDCl 3)d?6.85(s，2H)，6.06(s，1H)，4.65(m，1H)，3.32(m?1H)，2.61(m，4H)，2.28(s，3H)，2.14(s，3H)，2.12(s，2H)，2.06(s，6H)，1.71(m，2H)，1.46(m，2H)，0.96(t，3H)，0.87(t，3H)ppm
Embodiment 305
N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-1-propyl group-butane-1, the 2-diamines
1H?NMR(CDCl 3)d?6.85(s，2H)，6.11(s，1H)，4.21(d，1H)，3051(q，1H)，2.79(m，2H)，2.62(m，2H)，2.28(s，3H)，2.13(s，6H)，2.06(s，6H)，1.62(m，2H)，1.54(m，2H)，0.97(t，3H)，0.91(t，3H)ppm
Embodiment 306
N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-1-(2-methoxyl group-ethyl)-butane-1, the 2-diamines
1H?NMR(CDCl 3)d?6.85(s，2H)，6.11(s，1H)，4.18(d，1H)，3.51(m，3H)，3.35(s，2H)，2.82(m，4H)，2.28(s，3H)，2.14(s，6H)，2.06(s，6H)，1.62(m，2H)，0.97(t，3H)ppm
Embodiment 307
N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-N-1-furans-2-ylmethyl-butane-1, the 2-diamines
1HNMR(CDCl 3)7.36(s，1H)，6.85(s，2H)，6.32(d，1H)，6.24(d，1H)，6.09(s，1H)，4.15(d，1H)，3.84(d，2H)，3.58(m?1H)，2.79(m，2H)，2.28(s，3H)，2.13(d，6H)，2.05(s，6H)，1.62(m，2H)，0.95(t，3H)ppm
Embodiment 308
N-1-cyclopropyl methyl-N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-butane-1, the 2-diamines
1HNMR(CDCl 3)6.85(s，2H)，6.14(s，1H)，4.39(m，1H)，3.70(m，1H)，3.01(m，2H)，2.67(d，2H)，2.28(s，3H)，2.20(s，3H)，2.14(s，3H)，2.05(s，6H)，1.71(m，2H)，0.98(t.3H)，0.55(d，2H)，0.21(d，2H)ppm.
Embodiment 309
[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-(1-thiazolidine-3-ylmethyl-propyl group)-amine
1HNMR(CDCl 3)6.85(s，2H)，6.07(s，1H)，4.21(d，1H)，4.06(d，2H)，3.41(m，1H)，3.07(m，2H)，2.89(m，2H)，2.52(m，2H)，2.28(s，3H)，2.15(d，6H)，2.06(s，6H)，1.75(m，1H)，1.66(m，1H0，0.98(t，3H)ppm
Embodiment 310
N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-butane-1, the 2-diamines
Under 0 ℃, in the solution of toluene, add diphenyl phosphoryl azide and 1,8-diazabicyclo [3,4,0] ten-carbon-7-alkene to (1-methylol-propyl group)-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amine.The mixture that obtains is at room temperature stirred 30min, heat 75 ℃ then and spend the night.Reaction mixture is adopted the water quenching and adopts dichloromethane extraction.Organic layer is separated, and drying concentrates and uses 1: 1 dichloromethane/hexane to arrive methylene dichloride as eluent, by silica gel Biotage purifying, obtain into light yellow oil (1-azido-methyl-propyl group)-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amine.Adopt the triphenylphosphine reduction to obtain title compound oil.1H?NMR
(CDCl 3)d?6.86(s，2H)，6.11(s，1H)，4.02(d，1H)，3.40(q，1H)，2.84(m，2H)，2.28(s，3H)，2.13(s，
6H)，2.06(s，6H)，1.61(m，2H)，0.98(t，3H)ppm
Embodiment 311
1-{2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl amino]-butyl }-3-ethyl-urea
With N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-butane-1,2-diamines and the ethyl isocyanate mixture in ethylene dichloride at room temperature stirs and spends the night.Standard is handled and purifying obtains title compound.APCI[M+1]＝399.3，1H?NMR(CDCl 3)
Embodiment 312
N-{2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl amino]-butyl }-Toluidrin
With N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-butane-1,2-diamines and the methylsulfonyl chloride mixture in ethylene dichloride at room temperature stirs and spends the night.Standard is handled and purifying obtains title compound.APCI[M+1]＝406.2，1H?NMR(CDCl 3)
Embodiment 313
N-{2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl amino]-butyl }-ethanamide
With N-2-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-butane-1,2-diamines and the Acetyl Chloride 98Min. mixture in ethylene dichloride at room temperature stirs and spends the night.Standard is handled and purifying obtains title compound.APCI[M+1]＝370.3，1H?NMR(CDCl 3)
Embodiment 314
Cyclopropyl methyl-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-propyl group-amine
1H?NMR(CDCl 3)d?6.85(s，2H)，6.44(s，1H)，3.13(AB?q，2H)，2.90(d，2H，J＝8Hz)，2.28(s，3H)，2.24(s，3H)，2.16(s，3H)，2.05(s，6H)，1.47-1.65(m，2H)，0.86-0.92(m，4H)，0.42-0.46(m，2H)，0.04-0.08(m，2H)APCI+m/z＝353.3(M+1)
Embodiment 315
Cyclopropyl methyl-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-propyl group-amine
1H?NMR(CDCl 3)d?6.85(s，2H)，6.44(s，1H)，3.13(AB?q，2H)，2.90(d，2H，J＝8Hz)，2.28(s，3H)，2.24(s，3H)，2.16(s，3H)，2.05(s，6H)，1.47-1.65(m，2H)，0.86-0.92(m，4H)，0.42-0.46(m，2H)，0.04-0.08(m，2H)
APCI+m/z＝353.3(M+1)
Embodiment 316
3,6-dimethyl-4-(2-methyl-aziridine-1-yl)-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
1H?NMR(CDCl 3)d?6.86(s，2H)，6.29(s，1H)，2.31(sa，3H)，2.29(s，3H)，2.19(m，1H)，2.15(s，3H)，2.10(m，2H)，2.04(s，6H)，1.44(d，?3H，J＝5Hz)
Embodiment 317
4-(2-methoxymethyl-tetramethyleneimine-1-yl)-3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
1H?NMR(CDCl 3)d?6.86(s，2H)，6.34(s，1H)，3.99(q，1H，J＝4Hz)，3.67(m，1H)，3.49(dd，1H，J＝9Hz，4Hz)，3.32(s，3H)，3.15(m，2H)2.29(s，3H)，2.24(s，3H)，2.16(s，3H)，2.06(s，6H)，1.78-1.97(m，4H)ppm.
Embodiment 318
[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-(tetrahydrochysene-furans-3-yl)-amine
1H?NMR(CDCl 3)d?7.04(s，2H)，6.11(s，1H)，4.27(brs，1H)，3.7-4.1(m，4H)，2.2-2.4(m，1H0，2.08(s，6H)，2.07(s，6H)，1.94(m，1H)ppm.
Embodiment 319
[1-(tertiary butyl-dimethyl-silane oxygen ylmethyl-propyl group]-[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?6.85(s，2H)，6.07(s，1H)，3.71(m，2H)，3.39(m，1H)，2.28(s，3H)，2.16(s，3H)，2.09(s，3H)，2.06(s，6H)，1.70(m，2H)，0.91(s?9H)ppm
Embodiment 320
[3,6-dimethyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-4-yl]-ethyl-(2-tetramethyleneimine-1-base-ethyl)-amine
1H?NMR(CDCl 3)d?6.86(s，2H)，6.44(s，1H)，3.25-3.30(m，2H)，3.12(q，2H，J＝7Hz)，2.56-2.66(m，6H)，2.29(s，3H)，2.23(s，3H)，2.17(s，3H)，2.05(s，6H)，1.80(br?s，4H)，1.09(t，3H，J＝7Hz)
13C?NMR(CDCl 3)d.
APCI+m/z＝382(M+1)
Embodiment 321
4-[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-phenylformic acid
In-78 ℃ of solution, add n-BuLi at the intermediate of dry THF.Under this temperature, stir after the 10min, CO 2(g) bubbling joins in the reaction mixture.The mixture that obtains is stirred 2hr down at-78 ℃, be warmed up to room temperature gradually.Mixture is adopted rare HCl quenching and adopts dichloromethane extraction.Organic layer is separated, drying, concentrated and purifying obtains the title compound into white solid, mp.168.4 ℃.1HNMR(CDCl 3)7.58(s，2H)，6.36(s，1H)，4.24(m，1H)，2.35(s，3H)，2.22(s，3H)，2.14(s，6H)，1.75(m，4H)，0.99(t，6H)ppm.
Be prepared as follows embodiment 322-326 according to following general step: at the 4-[4-of anhydrous methylene chloride (1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3, add SOCl in 5-dimethyl-benzoic solution 2At room temperature stir 1hr.Mixture is concentrated to dry so that corresponding acyl chlorides to be provided.Adopt suitable nucleophilic reagent (as, NH acyl chlorides 3, MeNH 2, Me 2NH, EtNH 2, or methyl alcohol) quenching and at room temperature stirring so that title compound to be provided:
Embodiment 322
4-[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-benzamide
1H?NMR(CDCl 3)d?7.51(s，2H)，6.32(s，1H)，6.2(brs，1H)，5.7(brs，1H)，4.20(m，1H)，2.22(s，3H)，2.19(s，3H)，2.12(s，6H)，1.72(m，4H)，0.97(t，6H)ppm.
Embodiment 323
4-[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3,5, N-trimethylammonium-benzamide
1H?NMR(CDCl 3)d?7.43(s，2H)，6.30(s，1H)，6.19(brs，1H)，4.19(m，1H)，2.95(d，3H)，2.19(s，3H)，2.18(s，3H)，2.10(s，6H)，1.71(m，4H)，0.97(t，6H)ppm.
Embodiment 324
4-[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3,5, N, N-tetramethyl--benzamide
1H?NMR(CDCl 3)d?7.12(s，2H)，6.30(s，1H)，4.18(m，1H)，3.09(s，3H)，3.05(s，3H)，2.18(s，6H)，2.10(s，6H)，1.71(m，4H)，0.97(t，6H)ppm.
Embodiment 325
N-ethyl-4-[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-benzamide
1H?NMR(CDCl 3)d?7.46(s，2H)，6.30(s，1H)，6.1(brs，1H)，4.19(m，1H)，3.48(m，2H)，2.18(s，6H)，2.12(s，6H)，1.72(m，4H)，1.25(t，3H)，0.97(t，6H)ppm.
Embodiment 326
4-[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-methyl benzoate
1H?NMR(CDCl 3)d?7.76(s，2H)，6.30(s，1H)，4.17(m，1H)，3.89(s，3H)，2.19(s，3H)，2.169(s，3H)，2.12(s，6H)，1.712(m，4H)，0.97(t，6H)ppm.
Be prepared as follows embodiment 327-329 according to following general step: at the 4-[4-of anhydrous methylene chloride (1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3, add SOCl in 5-dimethyl-benzoic solution 2At room temperature stir 1hr.Mixture is concentrated to dry so that corresponding acyl chlorides to be provided.Adopt suitable nucleophilic reagent (as, NH acyl chlorides 3, MeNH 2, or methyl alcohol) quenching and at room temperature stirring so that title compound to be provided:
Embodiment 327
4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-benzamide
1H?NMR(CDCl 3)d?7.51(s，2H)，6.2(brs，1H)，6.1(s，1H)，5.5(brs，1H)，3.9(d，1H)，3.3(m，1H)，2.19(s，3H)，2.14(s，6H)，2.12(s，3H)，1,7(m，2H)，1.5(m，2H)，0.96(t，6H)ppm.
Embodiment 328
4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3,5, N-trimethylammonium-benzamide
1H?NMR(CDCl 3)d?7.431(s，2H)，6.3(ds，1H)，6.091(s，1H)，3.8(d，1H)，3.35(m，1H)，2.96(d，3H)，2.16(s，3H)，2.12(s，9H)，1.65(m，2H)，1.53(m，2H)，0.95(t，6H)ppm.
Embodiment 329
4-[4-(1-ethyl-propyl group amino)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-methyl benzoate
1H?NMR(CDCl 3)d?7.751(s，2H)，6.08(s，1H)，3.89(s，3H)，3.80(d，1H)，3.34(m，1H)，2.13(s，6H)，2.11(s，6H)，1.66(m，2H)，1.54(m，2H)，0.95(t，6H)ppm.
Following embodiment 330-340 relates to other compound of general formula I of the present invention, wherein R 4Be-CN:
Embodiment 330
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-cigarette nitrile
APCI[M+1]358.3
Embodiment 331
4-(1-ethyl-propyl group amino)-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-cigarette nitrile
Calculated value C:71.36; H:7.70; N:11.89; Measured value C:71.16, H:8.09, N:11.47; HNMR (CDCl 3) 6.59 (s, 2H), 6.08 (s, 1H), 4.74 (d, 1H), 3.78 (s, 3H), 3.38 (m, 1H), 2.18 (s, 3H), 2.10 (s, 6H), 1.64 (m, 2H), 1.55 (m, 2H), 0.96 (t, 6H) ppm.
Embodiment 332
4-(1-ethyl-propyl group amino)-6-methyl-2-(2,4,6-trimethylammonium-pyridin-3-yl oxygen)-cigarette nitrile
By heating 2-chloro-4-(1-ethyl-propyl group amino)-6-methyl-cigarette nitrile and 2,4 in NMP, 6-trihydroxy--3-pyridine, preparation title compound.
1HNMR(CDCl 3)7.02(m，1H)，6.13(s，1H)，4.81(d，1H)，3.40(m，1H0，2.67(s，3H0，2.48(s，3H0，2.25(s，3H)，2.16(s，3H)，1.68(m，4H)，0.97(t，6H)ppm
Embodiment 333
2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6-methyl-cigarette nitrile
1HNMR(CDCl 3)6.59(s，2H)，6.11(s，1H)，5.08(d，1H)，3.78(s，3H)，3.56(m，1H)，3.47(m，1H)，3.38(s，3H)，2.19(s，3H)，2.10(s，6H)，1.61(m，2H)，0.99(t，3H)ppm
Embodiment 334
2-(4-bromo-2,6-dimethyl-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-cigarette nitrile
1H?NMR(CDCl 3)d?7.19(s，2H)，6.09(s，1H)，4.77(d，1H)，3.39(m，1H)，2.18(s，3H)，2.10(s，6H)，1.65(m，2H)，1.55(m，2H)，0.96(t，3H)ppm.
Embodiment 335
4-[3-cyano group-4-(1-ethyl-propyl group amino)-6-methyl-pyridine-2-base oxygen]-3-methoxyl group-methyl benzoate
APCI[M+1]＝384.2，1H?NMR(CDCl 3)
Embodiment 336
4-[3-cyano group-4-(1-ethyl-propyl group amino)-6-methyl-pyridine-2-base oxygen]-3-methoxyl group-benzamide
1H?NMR(CDCl 3)d?7.52(s，1H)，7.32(d，1H)，7.16(d，1H)，6.25(brs，1H)，6.12(s，1H)，5.8(brs，1H)，4.78(d，1H)，3.80(s，3H)，3.39(m，1H)，2.20(s，3H)，1.67(m，2H)，?1.55(m，2H)，0.95(t，3H)ppm.
Embodiment 337
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6-methyl-cigarette nitrile
1H?NMR(CDCl 3)d?7.03(s，2H)，6.12(s，1H)，5.08(d，1H)，3.47(m，1H)，3.43(m，2H)，3.38(s，3H)，2.18(s，3H)，2.09(s，6H)，1.76(m，2H)，1.61(m，2H)，0.99(t，6H)ppm.
Embodiment 338
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-[(1-methoxymethyl-propyl group)-methyl-amino)-6-methyl-cigarette nitrile
1H?NMR(CDCl 3)d?7.03(s，2H)，6.27(s，1H)，4.33(m，1H)，3.59(m，1H)，3.52(m，1H)，3.35(s，3H)，3.06(s，3H)，2.16(s，3H)，2.11(s，6H)，1.69(m，4H)，0.97(t，6H)ppm..
Embodiment 339
2-(4-chloro-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-cigarette nitrile
1H?NMR(CDCl 3)d?7.04(d，1H，J＝9Hz)，6.91-6.94(m，2H)，6.10(s，1H)，4.73(d，1H，J＝9Hz)，3.75(s，3H)，3.35-3.38(m，1H)，2.19(s，3H)，1.47-1.70(m，4H)，0.95(t，6H，J＝8Hz)APCI+m/z＝360.1(M+1)，362.1(M+3)
Embodiment 340
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-cigarette nitrile
1H?NMR(CDCl 3)d?7.06-7.09(m，2H)，6.98-7.00(m，1H)，6.10(s，1H)，4.73(br?d，1H)，3.75(s，3H)，3.35-3.42(m，1H)，2.21(s，3H)，1.43-1.72(m，4H)，0.95(t，6H，J＝7Hz)ppm.
Other embodiments of the invention are as follows:
Embodiment 341
[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl group)-amine
1H?NMR(CDCl 3)d?7.05(s，2H)，6.04(s，1H)，5.33(s，1H)，4.26(br?d，1H)，3.34-3.39(m，1H)，3.31(s，6H)，2.31(s，3H)，2.12(s，6H)，1.47-1.61(m，4H)，0.89(t，6H，J＝8Hz)ppm.
Embodiment 342
[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-3-methylamino methyl-pyridin-4-yl]-(tetrahydrochysene-furans-3-yl)-amine
1H?NMR(CDCl 3)d?7.03(s，2H)，6.08(s，1H)，4.18(s，2H)，3.8-4.2(m，5H)，2.57(s，3H)，2.2-2.4(m，2H)，2.15(s，3H)，2.04(s，6H)ppm.
Embodiment 343
[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-yl)-pyridin-3-yl]-amine
1H?NMR(CDCl 3)d?7.02(s，2H)，6.10(s，1H)，5.49(brs，1H)，4.89(t，2H)，4.12(brs，1H)，4.01(m，2H)，3.99(m，1H)，3.75(m，1H)，2.30(m，1H)，2.16(s，3H)，2.05(s，6H)，1.95(m，1H)ppm.
Embodiment 344
2-[2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-base is amino]-4-methyl sulfenyl-Ding-1-alcohol
1H?NMR(CDCl 3)d?7.06(s，2H)，6.29(s，1H)，5.47(s，1H)，3.6-3.8(m，2H)，3.5(m，1H)，2.38(s，3H)，2.11(s，6H)，2.03(s，3H)，1.87(m，1H)，1.69(m，1H)ppm.
Preparation A
(6-chloro-2-methyl-5-nitro-pyrimidine-4-yl)-(2,4,6-trimethylammonium-pyridin-3-yl)-amine
With 2-methyl-5-nitro-4, and 6-two chloro-pyrimidines (208mg, 1.00mmol) solution in the 2.5ml acetonitrile adopts 2,4, and (273mg 2mmol) handles 6-trimethylammonium-3-amino-pyridine, at room temperature stirs 2 hours.Mixture is adopted the water quenching and adopts ethyl acetate extraction.Organic layer is adopted the salt water washing, the dry and concentrated resistates that obtains.The use chloroform as eluent, by silica gel chromatography, obtains the title compound (110mg, 36%) into orange oil with resistates to 6% methyl alcohol in chloroform. 1HNMR(CDCl 3)δ8.78(brs，1H)，6.97(s，1H)，2.54(s，3H)，2.43(s，3H)，2.40(s，3H)，2.17(s，3H)ppm.
Preparation B
2-chloro-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid
At water with in the diox mixture, at room temperature, by 2-chloro-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester and LiOH.H 2The reaction of O, the preparation title compound.Required product is acidified to pH3 and adopts ethyl acetate extraction.The organic layer drying is concentrated to drying.After adopting the ethyl acetate titration, obtain title compound with white crystal.Mp.164-165 ℃; Ultimate analysis C 12H 17Cl 2O 2Calculated value C, 56.14; H, 6.67; N, 10.91; Measured value: C, 56.40; H, 6.53; H, 10.93.
Preparation C
4-chloro-6-ethyl-3-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-1-oxide compound
In the 2 solution in dry THF, add NaH and also at room temperature stirred 20 minutes.Add 2, the solution of 4-two chloro-6-ethyl-3-methyl-pyridine-1-oxide compounds and with the heating 1.5 hours under refluxing of the mixture that obtains.With the mixture cool to room temperature, adopt the water quenching, adopt ethyl acetate extraction.Organic layer is separated, and drying obtains title compound with concentrating, and it can be directly used in the reaction of next step.
Preparation D
4-chloro-6-ethyl-3-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
In the solution of methylene dichloride, add PCl to 4-chloro-6-ethyl-3-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine-1-oxide compound 3And the mixture that obtains heated 20min, cool to room temperature under refluxing.Mixture is concentrated to drying.Use standard step to handle resistates and obtain title compound.After silica gel purification, separate white solid and obtain title compound.Mp.42-44 ℃. ultimate analysis C 17H 20CINO calculated value C, 70.46; H, 6.96; N, 4.83; Measured value, C, 70.35; H, 7.13; N, 4.58.
Preparation E
2-[4-chloro-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridin-3-yl methyl]-dimethyl malonate
In methyl alcohol, by making 4-chloro-3-chloromethyl-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine and dimethyl malonate/NaH reaction, preparation title compound.Title compound is separated into water white oil.
Preparation F
4-chloro-3,6-dimethyl-2-(2,4,6-trimethylammonium-3-pyridyl)-pyridine
Preparation G
2-chloro-4-(1-methoxymethyl-propoxy-)-6-methyl-Nikithan
1H?NMR(CDCl 3)d?6.72(s，1H)，4.5(m，1H)，4.4(q，2H)，3.49(d，2H)，3.31(s，3H)，2.46(s，3H)，1.68(m，2H)，1.34(t，3H)，0.93(t，3H)ppm.
Preparation H
2-chloro-4-(1-methoxymethyl-propoxy-)-6-methyl-nicotinic acid
1H?NMR(CDCl 3)d?6.81(s，2H)，4.51(m，1H)，3.60(m，2H)，3.40(s，3H)，2.55(s，3H)，1.77(m，2H)，1.02(t，3H)ppm.
Preparation I
(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-methoxymethyl-propoxy-)-amine
Mp.63-65 ℃, ultimate analysis C 11H 16N 3O 3Cl calculated value C, 48.27; H, 5.89, N, 15.35; Measured value C, 48.65; H, 6.03, N, 15.11.
Preparation J
(5-bromo-6-chloro-2-methyl-pyrimidine-4-yl)-(2,4-two chloro-phenyl)-amine
Mp.165-167 ℃; Ultimate analysis C 11H 7BrCl 3Calculated value: C, 35.95; H, 1.92; N, 11.43; Measured value: C, 36.41; H, 1.91; N, 11.05.
Preparation K
(6-chloro-2-methyl-pyrimidine-4-yl)-(2,4-two chloro-phenyl)-amine
Mp.134-136 ℃; Ultimate analysis C 11H 8Cl 3N 3Calculated value: C, 45.79; H, 2.79; N, 14.56; Measured value: C, 45.91; H, 2.69; N, 14.50.
Preparation L
[4-chloro-6-(1-ethyl-propyl group amino)-2-methyl-pyrimidine-5-yl]-ethyl acetate
Mp.78-80 ℃, ultimate analysis C 14H 22ClN 3O 2Calculated value: C, 56.09; H, 7.40; N, 14.02; Measured value: C, 56.31; H, 7.60; N, 13.94.
Preparation M
2-[4-bromo-2-methyl-6-(2,4,6-trimethylammonium-phenoxy group)-pyrimidine-5-yl]-ethyl propionate
1H?NMR(CDCl 3)d?6.86(s，2H)，4.2-4.359m，2H)，4.C-4.15(m，1H)，2.4(s，3H)，2.28(s，3H)，1.99(s，3H)，1.97(s，3H)，1.58(d，3H)，1.22(t，3H)ppm.
Preparation N
2-(4,6-two bromo-2-methyl-pyrimidine-5-yls]-ethyl propionate
1H?NMR(CDCl 3)4.36(m，1H)，4.19(m，2H)，2.68(s，3H)，1.549d，3H)，1.22(t，3H)ppm.
Preparation O
4-bromo-3-methoxyl group-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
1H?NMR(CDCl 3)d?6.92(s，1H)，6.87(s，2H)，4.00(s，3H)，2.299s，3H)，2.18(s，3H)，2.059s，6H)ppm.
Preparation P
4-bromo-2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridine
1H?NMR(CDCl 3)d?7.04(s，2H)，6.97(s，1H)，2.42(s，3H)，2.17(s，3H)，2.03(s，6H)ppm.
Preparation Q
4-bromo-2-(2,4-two chloro-6-methyl-phenoxy groups)-3-methoxyl group-6-methyl-pyridine
1H?NMR(CDCl 3)d?7.3(d，1H)，7.18(d，1H)，4.0(s，3H)，2.2(s，3H)，2.15(s，3H)ppm.
Preparation R
4-bromo-2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxyl group-6-methyl-pyridine
Ultimate analysis C 15H 15BrCINO 2Calculated value: C, 50.52; H, 4.24; N, 3.93; Measured value: C, 50.52; H, 4.37; N, 3.91.
Preparation S
4-bromo-2-(4-chloro-2-methoxyl group-phenoxy group)-3-methoxyl group-6-methyl-pyridine
1H?NMR(CDCl 3)d?6.9-7.1(m，4H)，3.94(s，3H)，3.71(s，3H)，2.21s，3H)ppm.
Preparation T
4-bromo-2-(3-chloro-2,6-dimethoxy-phenoxy group)-3-methoxyl group-6-methyl-pyridine
1H?NMR(CDCl 3)d?7.17(d，1H)，6.96(s，1H)，6.66(d，1H)，3.97(s，3H)，3.79(s，3H)，3.70(s，3H)，2.18(s，3H)ppm.
Preparation U
4-bromo-3-methoxyl group-6-methyl-2-(2,4,6-trimethylammonium-phenoxy group)-pyridine
1H?NMR(CDCl 3)d?6.90(s，1H)，6.19(s，2H)，3.968(s，3H)，3.80(s，3H)，3.71(s，6H)，2.18(s，3H)ppm.
Preparation V
4-bromo-3-methoxyl group-2-(4-methoxyl group-2,6-dimethyl-phenoxy group)-6-methyl-pyridine
1H?NMR(CDCl 3)d?6.92(s，1H)，6.60(s，2H)，3.98(s，3H)，3.78(s，3H)，2.18(s，3H)，2.07(s，6H)ppm.
Preparation W
4-bromo-2-(4-chloro-2,6-dimethyl-phenoxy group)-3-oxyethyl group-6-methyl-pyridine
1H?NMR(CDCl 3)d?7.099s，2H)，7.00(s，1H)，4.28(q，2H)，2.22(s，3H)，2.10(s，6H)，1.51(t，3H)ppm.
Preparation X
4-bromo-3,6-dimethyl-2-(2,4,6-trimethoxy-phenoxy group)-pyridine
1H?NMR(CDCl 3)d?6.99(s，1H)，6.25(s，2H)，3.86(s，3H)，3.77(s，6H)，2.47(s，3H).2.25(s，3H)ppm.
Preparation Y
4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl isophthalic acid-oxygen-nicotinic acid methyl ester
Preparation RR
4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-nicotinic acid methyl ester
1H?NMR(CDCl 3)d?7.03(s，2H)，6.869s，1H)，3.969s，3H)，2.259s，3H)，2.05(s，6H)ppm.
Preparation Z
4-chloro-6-methyl-2-(2,4,6-trimethoxy-phenoxy group)-pyridine-3-carbonyl aldehyde
In methylene dichloride, at room temperature, by adopting pyridinium chlorochromate oxidation 4-chloro-6-methyl-2-(2,4,6-trimethoxy-phenoxy group)-pyridin-3-yl-methyl alcohol, the preparation title compound.After column chromatography, required product separation is obtained green solid (80% yield).
1H?NMR(CDCl 3)d?10.66(s，1H)，6.91(s，3H)，2.31(s，3H)，2.07(s，3H)ppm.
Preparation AA
2-(4-bromo-2,6-dimethyl-phenoxy group)-4-chloro-6-methyl-nicotinic acid methyl ester
Mp.108-110 ℃; Ultimate analysis C 16H 15BrCINO 3Calculated value, 49.96; H, 3.93; N, 3.64; Measured value: C, 50.07; H, 4.10; N, 3.57.
Preparation BB
4-chloro-2-(4-chloro-2-methoxyl group-phenoxy group)-6-methyl isophthalic acid-oxygen-nicotinic acid methyl ester
Mp.117-120 ℃, ultimate analysis C 15H 13NO 5Cl 2Calculated value: C, 50.30; H, 3.66; N, 3.91; Measured value: C, 50.41; H, 3.55; N, 4.00.
Preparation CC
4-chloro-2-(4-chloro-2-methoxyl group-phenoxy group)-6-methyl-nicotinic acid methyl ester
Mp.92-93 ℃, ultimate analysis C 15H 13NO 4Cl 2Calculated value: C, 52.65; H, 3.83; N, 4.09; Measured value: C, 52.34; H, 3.85; N, 4.13.
Preparation DD
[1-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-propyl group]-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3,6-dimethyl-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?7.06(s，2H)，6.12(s，1H)，4.3(d，1H)，3.6-3.8(m，2H)，3.4(m，1H)，2.16(s，3H)，2.14(s，3H)，2.10(s，6H)，1.5-1.8(m，2H)，1.03(t，3H)，0.95(s，9H)，0.09(m，6H)ppm.
By similar in appearance to the method for in embodiment 160, describing, use suitable 4-bromo-2-(substituent phenoxy)-6-alkyl or alkoxyl group-pyridine and 1-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-propylamine, be prepared as follows compound.
Preparation EE
[1-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-propyl group]-[3-methoxyl group-6-methyl-2-(2,4,6-trimethoxy-phenoxy group)-pyridine-4-(S)-yl]-amine
1H?NMR(CDCl 3)d?6.84(s，2H)，6.08(s，1H)，4.8(d，1H)，3.88(s，3H)，3.5-3.7(m，2H)，3.3(m，1H)，2.27(s，3H)，2.099s，3H)，2.07(s，6H)，1.75(m，1H)，1.55(m，1H)，0.97(t，3h)，0.89(s，9H)，0.04(s，6H)ppm.
Preparation FF
[1-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-propyl group]-[2-(4-chloro-2,6-dimethyl-phenoxy group)-3-methoxyl group-6-methyl-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?7.02(s，2H)，6.10(s，1H)，4.80(d，1H)，3.87(s，3H)，3.6-3.7(m，2H)，3.30(m，1H)，2.09(s，3H)，2.08(s，6H)，1.75(m，1H)，1.55(m，1H)，0.97(t，3H)，0.89(s，9H)，0.03(s，6H)ppm.
Preparation GG
4-[1-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-propyl group amino]-2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-pyridine-3-alcohol
1H?NMR(CDCl 3)d?7.01(s，2H)，6.15(s，1H)，4.46(d，1H)，3.7(m，1H)，3.6(m，1H)，3.4(m，1H)，2.09(s，3H)，2.08(s，6H)，1.5-1.8(m，2H)，1.06(s，9H)，0.98(t，3H)，0.24(s，6H)ppm.
Preparation HH
[1-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-propyl group]-[3-methoxyl group-6-methyl-2-(2,4,6-trimethoxy-phenoxy group)-pyridin-4-yl]-amine
1H?NMR(CDCl 3)d?6.19(s，2H)，6.09(s，1H)，3.86(s，3H)，3.80(s，3H)，3.73(s，6H)，3.3(m，1H)，2.16(s，3H)，1.75(m，1H)，1.5(m，1H)，0.95(t，3H)，0.89(s，9H)，0.04(s，6H)ppm.
Preparation II
4-{4-[1-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-propyl group amino]-3-methoxyl group-6-methyl-pyridine-2-base oxygen }-3,5-dimethyl-yl]-benzonitrile
1H?NMR(CDCl 3)d?7.40(s，2H)，6.19(s，1H)，4.90(brs，1H)，3.87(s，3H)，3.70(m，2H)，3.3(m，1H)，2.19(m，9H)，1.5-1.8(m，2H)，1.02(t，3H)，093(s，9H)，0.09(s，6H)ppm.

Claims (24)

1. the compound that has following general formula Or
Figure A0180384600022
Or its pharmaceutical salts, wherein dotted line is represented two keys of choosing wantonly, condition is to work as C ---When the dotted line among the G is represented two key, N (R then 6) ---Dotted line among the C is not represented two keys; And condition is as N (R 6) ---When the dotted line among the C is represented two key, R 6In general formula III, do not exist and C ---Dotted line among the G is not represented two keys;
A is-CR 7Or N;
B is-NR 1R 2,-CR 1R 2R 11,-C (=CR 2R 12) R 1,-NHCHR 1R 2,-OCHR 1R 2,-SCHR 1R 2,-CHR 2OR 1,-CHR 1OR 2,-CHR 2SR 1,-C (S) R 2,-C (O) R 2,-CHR 2NR 1R 2,-CHR 1NHR 2,-CHR 1N (CH 3) R 2, or-NR 12NR 1R 2
Work as C ---When the dotted line among the G was represented two key, then G was hydrogen, oxygen, sulphur, NH or N (C 1-C 4Alkyl);
Work as C ---When the dotted line among the G is not represented two key, C then ---G is C (H) (NH 2), CH 2, C (H) (methoxyl group), C (H) (oxyethyl group), C (H) (O (C 3-C 4Alkyl)), C (H) (halogen), C (H) (trifluoromethoxy), C (H) (methyl), C (H) (ethyl), C (H) (C 3-C 4Alkyl), C (H) (S (C 1-C 4Alkyl)) C (C, 1-C 4Alkyl) (C 1-C 4Alkyl), cyclopropyl, C (H) (cyclopropyl), sulfo-methoxyl group, C (H) (NH 2), C (H) (NHCH 3), C (H) (N (CH 3) 2) or C (H) (trifluoromethyl);
C wherein ---The cyclopropyl of G, methoxyl group, oxyethyl group, C 3-C 4Alkyl and C 1-C 4Alkyl can randomly be replaced by an OH, methoxyl group or trifluoromethoxy, or randomly 1-6 fluorine atom replaces;
Y is CH or N;
Z be NH, O, S ,-N (C 1-C 2Alkyl) ,-NC (O) CF 3, or-C (R 13R 14), R wherein 13And R 14Separately, randomly, be hydrogen, trifluoromethyl or methyl, or R 13And R 14One be that cyano group and another are hydrogen or methyl, or-C (R 13R 14) be cyclopropyl, or Z is nitrogen or CH and formation and R 5Five yuan of condensed or hexa-member heterocycle, this ring comprise that randomly two or three are independently selected from oxygen, nitrogen, NR 12, and S (O) mIn addition assorted member, and randomly comprise 1-3 two keys and randomly by halogen, C 1-C 4Alkyl ,-O (C 1-C 4Alkyl), NH 2, NHCH 3, N (CH 3) 2, CF 3, or OCF 3Replace, condition is that this ring does not comprise any-S-S-,-S-O-,-N-S-or-O-O-key and not comprising more than two oxygen or S (O) mThe xenogenesis member;
R 1Be C (O) H, C (O) (C 1-C 6Alkyl), C (O) (C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl), C (O) (C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), C (O) (C 1-C 6Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-C (O) (C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl), C 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 4-C 8Heterocyclylalkyl, (C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-(C 1-C 6Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl) or-the O-aryl or-O-(C 1-C 6Alkylidene group)-aryl; Wherein aryl, C 4-C 8Heterocyclylalkyl, C 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkylidene and C 1-C 6Alkylidene group can each randomly replaced independently by 1-6 fluorine and can each independently randomly by one or two substituent R 8Replace R 8Be independently selected from C 1-C 4Alkyl, C 3-C 8Cycloalkyl, hydroxyl, chlorine, bromine, iodine, CF 3,-O-(C 1-C 6Alkyl) ,-O-(C 3-C 5Cycloalkyl) ,-O-CO-(C 1-C 4Alkyl) ,-O-CO-NH (C 1-C 4Alkyl) ,-O-CO-N (R 24) (R 25) ,-N (R 24) (R 25) ,-S (C 1-C 4Alkyl) ,-S (C 3-C 5Cycloalkyl) ,-N (C 1-C 4Alkyl) CO (C 1-C 4Alkyl) ,-NHCO (C 1-C 4Alkyl) ,-COO (C 1-C 4Alkyl) ,-CONH (C 1-C 4Alkyl) ,-CON (C 1-C 4Alkyl) (C 1-C 2Alkyl), CN, NO 2,-OSO 2(C 1-C 4Alkyl), S +(C 1-C 6Alkyl) (C 1-C 2Alkyl) I -,-SO (C 1-C 4Alkyl) and-SO 2(C 1-C 4Alkyl); And R wherein 1C 1-C 6Alkyl, C 1-C 6Alkylidene group, C 5-C 8Cycloalkyl, C 5-C 8Cycloalkylidene and C 5-C 8The Heterocyclylalkyl part can randomly comprise 1-3 two keys or triple bond; R wherein 8C 1-C 4Moieties and C 1-C 6Moieties can be chosen wantonly independently by hydroxyl, amino, C 1-C 4Alkyl, aryl ,-CH 2-aryl, C 3-C 5Cycloalkyl or-O-(C 1-C 4Alkyl) replaces and can randomly be replaced and can randomly comprise 1-2 pair keys or triple bond by 1-6 fluorine; R wherein 1Each heterocyclic radical comprise 1-3 and be selected from oxygen, S (O) m, nitrogen and NR 12Hetero moiety;
R 2Be hydrogen, C 1-C 12Alkyl, C 3-C 8Cycloalkyl, C 4-C 6Heterocyclylalkyl ,-(C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-(C 1-C 6Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl), aryl ,-(C 1-C 6Alkylidene group) aryl or-(C 3-C 8Cycloalkylidene) (aryl); Each above-mentioned R wherein 2Group can randomly be selected from chlorine, fluorine and C by 1-3 1-C 6The substituting group of alkyl replaces, and wherein one of 1-3 substituting group can further be selected from bromine, iodine, C 1-C 6Alkoxyl group ,-OH ,-O-CO-(C 1-C 6Alkyl) ,-O-CO-N (C 1-C 4Alkyl) (C 1-C 2Alkyl) ,-S (C 1-C 6Alkyl) ,-S (O) (C 1-C 6Alkyl) ,-S (O) 2(C 1-C 6Alkyl), S +(C 1-C 6Alkyl) (C 1-C 2Alkyl) I -, CN and NO 2, and R wherein 2C 1-C 12Alkyl ,-(C 1-C 6Alkylidene group) ,-(C 5-C 8Cycloalkyl) ,-(C 5-C 8Cycloalkylidene) and-(C 5-C 8Heterocyclylalkyl) part can randomly comprise 1-3 two keys or triple bond; And R wherein 2Each Heterocyclylalkyl comprise 1-3 and be selected from oxygen, S (O) m, nitrogen and NR 12Hetero moiety;
Or work as R 1And R 2As at-NHCHR 1R 2,-OCHR 1R 2,-SCHR 1R 2,-CHR 1R 2, or NR 1R 2When middle, the R of B 1And R 2Can form 5 yuan of-8 yuan of rings, this ring can randomly comprise one or two pair key and one of them or two ring carbon can be randomly by oxygen, S (O) m, and NR 12Replace; And this carbocyclic ring can randomly be selected from following substituting group by 1-3 and replace: hydroxyl, C 1-C 4Alkyl, fluorine, chlorine, bromine, iodine, CF 3,-O-(C 1-C 4Alkyl) ,-O-CO-(C 1-C 4Alkyl) ,-O-CO-NH (C 1-C 4Alkyl) ,-O-CO-NH (C 1-C 4Alkyl) (C 1-C 2Alkyl) ,-NH (C 1-C 4Alkyl) ,-N (C 1-C 2Alkyl) (C 1-C 4Alkyl) ,-S (C 1-C 4Alkyl) ,-N (C 1-C 4Alkyl) CO (C 1-C 4Alkyl) ,-NHCO (C 1-C 4Alkyl) ,-COO (C 1-C 4Alkyl) ,-CONH (C 1-C 4Alkyl) ,-CON (C 1-C 4Alkyl) (C 1-C 2Alkyl), CN, NO 2,-OSO 2(C 1-C 4Alkyl) ,-SO (C 1-C 4Alkyl) and-SO 2(C 1-C 4Alkyl), wherein one of this 1-3 substituting group can further be selected from phenyl;
R 3Be methyl, ethyl, fluorine, chlorine, bromine, iodine, cyano group, methoxyl group, OCF 3, NH 2,-NH (C 1-C 2Alkyl) ,-N (CH 3) 2,-NHCOCF 3,-NHCH 2CF 3, S (O) m(C 1-C 4Alkyl), CONH 2,-CONHCH 3,-CON (CH 3) 2,-CF 3, or CH 2OCH 3
R 4Be hydrogen, C 1-C 4Alkyl, C 3-C 5Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 5Cycloalkyl) ,-(C 3-C 5Cycloalkylidene) (C 3-C 5Cycloalkyl), cyano group, fluorine, chlorine, bromine, iodine ,-OR 24, C 1-C 6Alkoxyl group ,-O-(C 3-C 5Cycloalkyl) ,-O-(C 1-C 4Alkylidene group) (C 3-C 5Cycloalkyl) ,-O-(C 3-C 5-cycloalkylidene (C 3-C 5Cycloalkyl), CH 2SC (S) O (C 1-C 4Alkyl), CH 2OCF 3,-CF 3, amino, nitro ,-NR 24R 25,-(C 1-C 4Alkylidene group) OR 24,-(C 1-C 4Alkylidene group) Cl ,-(C 1-C 4Alkylidene group) NR 24R 25,-NHCOR 24,-NHCONR 24R 25,-C=NOR 24, NHNR 24R 25, S (O) mR 24,-C (O) R 24,-OC (O) R 24,-C (O) CN ,-C (O) NR 24R 25,-C (O) NHNR 24R 25, and-COO R 24, R wherein 4Alkyl and alkylidene group can randomly comprise one or two pair key or triple bond and can be independently randomly independently by 1-2 substituent R 10Replace R 10Be independently selected from hydroxyl, amino ,-NHCOCH 3,-NHCOCH 2Cl ,-NH (C 1-C 2Alkyl) ,-N (C 1-C 2Alkyl) (C 1-C 2Alkyl) ,-COO (C 1-C 4Alkyl) ,-COOH ,-CO (C 1-C 4Alkyl), C 1-C 6Alkoxyl group, C 1-C 3Alkylthio, cyano group and nitro and contain the substituting group that 1-4 is independently selected from fluorine and chlorine;
R 5Be aryl or heteroaryl and by 1-4 substituent R 27Replace R 27Be independently selected from halogen, C 1-C 10Alkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 1-C 4Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkyl) ,-(C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl), C 1-C 4Haloalkyl, C 1-C 4Halogenated alkoxy, nitro, cyano group ,-NR 24R 25,-NR 24COR 25,-NR 24CO 2R 26,-COR 24,-OR 25,-CONR 24R 25,-CO (NOR 22) R 23,-CO 2R 26,-C=N (OR 22) R 23, and S (O) mR 23This C wherein 1-C 10Alkyl, C 3-C 8Cycloalkyl, (C 1-C 4Alkylidene group), (C 3-C 8Cycloalkyl), (C 3-C 8Cycloalkylidene) and (C 4-C 8Heterocyclylalkyl) group can randomly be independently selected from following substituting group replacement: C by 1-3 1-C 4Alkyl, C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), C 1-C 4Haloalkyl, hydroxyl, C 1-C 6Alkoxyl group, nitro, halogen, cyano group ,-NR 24R 25,-NR 24COR 25,-NR 24CO 2R 26,-COR 24,-OR 25,-CONR 24R 25,-CO 2R 26,-CO (NOR 22) R 25, and S (O) mR 23R wherein 5That two adjacent substituting groups of group can form is saturated or unsaturated, be fused to R 5On 5-7 unit ring, this ring randomly comprises one, two, or three be independently selected from O, S (O) mWith the xenogenesis member of N, but without any-S-S-,-O-O-,-S-O-or-N-S-key and this ring can be randomly by C 1-C 4Alkyl, C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), C 1-C 4Haloalkyl, nitro, halogen, cyano group ,-NR 24R 25,-NR 24COR 25,-NR 24CO 2R 26,-COR 24,-OR 25,-CONR 24R 25,-CO 2R 26,-CO (NOR 26) R 25, and S (O) mR 23Replace; The optional substituent R of this 1-4 wherein 27One of can further be selected from-SO 2NH (C 1-C 4Alkyl) ,-SO 2NH (C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-SO 2NH (C 3-C 8Cycloalkyl) ,-SO 2NH (C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-SO 2N (C 1-C 4Alkyl) (C 1-C 2Alkyl) ,-SO 2NH 2,-NHSO 2(C 1-C 4Alkyl) ,-NHSO 2(C 3-C 8Cycloalkyl) ,-NHSO 2(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) and-NHSO 2(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl); And R wherein 5Alkyl and alkylidene group can randomly comprise two keys or triple bond independently;
R 6Be hydrogen, C 1-C 4Alkyl, C 3-C 8Cycloalkyl ,-(C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl) or-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), wherein this alkyl or cycloalkyl can randomly be replaced by a hydroxyl, methoxyl group, oxyethyl group or fluorin radical;
Or wherein compound is the compound of general formula I I, R 6And R 4(=O) group maybe can connect to form 3-8 unit carbocyclic ring, randomly comprises 1-3 two keys and randomly comprise one, two or three to be selected from oxygen, SO can to form oxo together m, N and NR 12The xenogenesis ring members, but do not comprise any-O-O-,-S-O-,-S-S-or-the N-S-key, and further randomly by C 1-C 4Alkyl or C 3-C 8Cycloalkyl substituted, wherein this C 1-C 4Alkyl substituent can randomly comprise two keys or triple bond;
R 7Be hydrogen, methyl, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl ,-O (C 1-C 2Alkyl) ,-O (cyclopropyl) ,-COO (C 1-C 2Alkyl) ,-COO (C 3-C 8Cycloalkyl) ,-OCF 3, CF 3,-CH 2OH or CH 2OCH 3
R 11Be hydrogen, hydroxyl, fluorine, oxyethyl group or methoxyl group;
R 12Be hydrogen or C 1-C 4Alkyl;
R 16And R 17Each is hydrogen, hydroxyl, methyl, ethyl, methoxyl group or oxyethyl group independently, except R 16And R 17Both are not methoxy or ethoxy simultaneously;
Or R 16And R 17Form oxo (=O) group together;
Or R 16And R 17Connection to be to form 3-8 unit carbocyclic ring, randomly comprises 1-3 two keys and randomly comprise to be selected from O, SO m, N and NR 12The xenogenesis ring members, but do not comprise any-O-O-,-S-O-,-S-S-or-N-S-key and further randomly by C 1-C 4Alkyl or C 3-C 6Cycloalkyl substituted, wherein this C 1-C 4Alkyl substituent can randomly comprise two keys or triple bond;
R 22Be independently selected from hydrogen, C in each case 1-C 4Alkyl, C 1-C 4Haloalkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl group, C 3-C 8Cycloalkyl ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) and-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl);
R 23Be independently selected from C in each case 1-C 4Alkyl, C 1-C 4Haloalkyl, C 2-C 8Alkoxyalkyl, C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), aryl ,-(C 1-C 4Alkylidene group) aryl, piperidines, tetramethyleneimine, piperazine, N methyl piperazine, morpholine and thiomorpholine;
R 24And R 25Be independently selected from hydrogen, C in each case 1-C 4Alkyl, C 1-C 4Haloalkyl, particularly CF 3, CHF 2, CF 2CF 3, or CH 2CF 3,-(C 1-C 4Alkylidene group) OH ,-(C 1-C 4Alkylidene group)-O-(C 1-C 4Alkyl) ,-(C 1-C 4Alkylidene group)-O-(C 3-C 5Cycloalkyl), C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl) ,-C 4-C 8Heterocyclylalkyl ,-(C 1-C 4Alkylidene group) (C 4-C 8Heterocyclylalkyl) ,-(C 3-C 8Cycloalkylidene) (C 4-C 8Heterocyclylalkyl), aryl and-(C 1-C 4Alkylidene group) aryl, wherein-C 4-C 8Heterocyclylalkyl can each independently randomly by aryl, CH 2-aryl or C 1-C 4Alkyl replaces, and can randomly comprise one or two pair key or triple bond; Or work as R 24And R 25Be as NR 24R 25,-C (O) NR 24R 25,-(C 1-C 4Alkylidene group) NR 24R 25, or-NHCONR 24R 25, NR then 24R 25Can further randomly form 4-8 unit heterocycle, randomly comprise one or two and be independently selected from S (O) m, oxygen, nitrogen and NR 12In addition assorted member and randomly comprise 1-3 two keys;
R 26Be independently selected from C in each case 1-C 4Alkyl, C 1-C 4Haloalkyl, C 3-C 8Cycloalkyl ,-(C 1-C 4Alkylidene group) (C 3-C 8Cycloalkyl) ,-(C 3-C 8Cycloalkylidene) (C 3-C 8Cycloalkyl), aryl and-(C 1-C 4Alkylidene group) (aryl); With
Wherein each m is 0,1 or 2 independently,
Condition be the Heterocyclylalkyl of general formula I, II, III compound do not comprise any-S-S-,-S-O-,-N-S-or-O-O-key and not comprising more than two oxygen or S (O) mThe xenogenesis member.
2. according to the compound of claim 1, R wherein 4Be-NHCH 2CF 3,-CONHNH 2,-CONHNHCH 3,-OCF 3, fluorine ,-OCHF 2,-OCH 2(C 3-C 5Cycloalkyl) ,-O-(C 3-C 5Cycloalkyl) ,-SCH 2(C 3-C 5Cycloalkyl) ,-S (C 3-C 5Cycloalkyl) ,-OCH 3,-CH 3,-CH 2CH 3, chlorine, bromine ,-CF 3,-CH 2OH ,-CH 2OCH 3,-CH 2OCF 3,-SCH 3,-S (O) CH 3,-S (O) 2CH 3,-C (O) CH 3,-NR 24R 25,-NO 2,-CH (OH) CH 3, or-CN.
3. according to the compound of claim 1, R wherein 4Be-C (O) NR 24R 25Or-C (O) NHNR 24R 25
4. according to the compound of claim 3, R wherein 24And R 25Be independently selected from hydrogen and C 1-C 4Alkyl.
5. according to the compound of claim 1, R wherein 4Be-(C 1-C 4Alkylidene group) NR 24R 25
6. according to the compound of claim 1, R wherein 4Be-COOCH 3Or-COOCH 2CH 3
7. according to the compound of claim 6, R wherein 4Be-COOCH 3
8. according to the compound of claim 1 general formula I, wherein Z is O; B is-NHCHR 1R 2, R wherein 1Be C (O) H, C (O) (C 1-C 6Alkyl) or-C 1-C 6Alkyl, wherein said C 1-C 6Alkyl randomly is independently selected from-C by 1-6 fluorine atom or one or two 1-C 4Alkyl, hydroxyl and-O-(C 1-C 6Alkyl) R 8Replace, and R wherein 2Be-C 1-C 12Alkyl randomly comprises 1-3 two keys or triple bond and randomly is selected from fluorine and C by 1-3 1-C 6The substituting group of alkyl replaces; R 5Be phenyl, pyridyl or pyrimidyl, be selected from following R by two or three 27Group replaces: halogen, (C 1-C 4Haloalkyl) ,-C (O) R 24,-OR 25,-C (O) NR 24R 25, and C 1-C 10Alkyl, it randomly is selected from hydroxyl, C 1-C 6Alkoxyl group and-NR 24R 251-3 substituting group, preferred substituting group replaces, and R 4Be-C (O) NR 24R 25
9. according to the compound of claim 1 general formula I, wherein Z is O; B is-NHCHR 1R 2, wherein-NHCHR 1R 2R 1Be C (O) H, C (O) (C 1-C 6Alkyl) or-C 1-C 6Alkyl, wherein this C 1-C 6Alkyl randomly is independently selected from-C by 1-6 fluorine atom or one or two 1-C 4Alkyl, hydroxyl and-O-(C 1-C 6Alkyl) R 8Replace and wherein-NHCHR 1R 2R 2Be-C 1-C 12Alkyl randomly comprises 1-3 two keys or triple bond and randomly is selected from fluorine and C by 1-3 1-C 6The substituting group of alkyl replaces; R 5Be phenyl, pyridyl or pyrimidyl, be selected from following R by two or three 27Group replaces: halogen, (C 1-C 4Haloalkyl) ,-C (O) R 24,-OR 25,-C (O) NR 24R 25, and C 1-C 10Alkyl, it randomly is selected from hydroxyl, C 1-C 6Alkoxyl group and-NR 24R 251-3 substituting group, preferred substituting group replaces, and R 4Be-NR 1R 2, wherein-NR 1R 2R 1Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl or-(C 1-C 6Alkylidene group) (C 3-C 8Cycloalkyl), and-NR 1R 2R 2Be-C 1-C 12Alkyl randomly comprises two keys of 1-3 or triple bond and randomly by 1-3 fluorine atom replacement.
10. according to the compound of claim 1, be selected from:
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methoxymethyl-propyl group amino)-6-methyl-niacinamide;
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-methoxyl group-propyl group amino)-6-methyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-ethyl-2-methoxyl group-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2-trifluoromethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide;
2-(4-chloro-2-trifluoromethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1S, 2R-1-ethyl-2-methoxyl group-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1S, 2S-1-ethyl-2-methoxyl group-propyl group amino)-6, N-dimethyl-niacinamide;
2-(4-bromo-2-methoxyl group-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-niacinamide;
4-[4-(1-ethyl-propoxy-)-3,6-dimethyl-pyridine-2-base oxygen]-3,5-dimethyl-benzamide;
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(1-methyl sulfenyl methyl-propyl group amino)-nicotinic acid methyl ester;
2-(4-chloro-2,6-dimethyl-phenoxy group)-4-(1-methylol-propyl group amino)-6-methyl-nicotinic acid methyl ester;
2-(4-bromo-2,6-dimethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-cigarette nitrile;
2-(4-chloro-2-trifluoromethoxy-phenoxy group)-4-(1-ethyl-propyl group amino)-6-methyl-nicotinic acid methyl ester; With
2-(4-chloro-2,6-dimethyl-phenoxy group)-6-methyl-4-(tetrahydrochysene-furans-3-base is amino)-nicotinic acid methyl ester;
And pharmaceutical salts.
11. pharmaceutical composition that is used for following treatment: (a) its treatment can be by antagonism CRF influence or the promoted obstacle or the state of an illness, include but not limited to induce or promoted obstacle, (b) be selected from the following obstacle or the state of an illness: struvite obstacle such as rheumatic arthritis and osteoarthritis, pain, asthma, psoriasis and allergy by CRF; The universality anxiety disorder, frightened, phobia, comprise social phobia, agoraphobia and specific phobia disease, obsessional idea and behavior disease, stress disorder after the wound, by stress reaction inductive somnopathy, the pain sensation such as fibromyalgia, affective disorder such as melancholia, comprise major depression, single-shot is done depressed, the recurrent depression, child abuse inductive depression, the affective disorder relevant with syndrome before the menstruation, and postpartum depression, depression, bipolar disorder, cyclothymia, chronic tired syndrome, the headache of stress-induced, cancer, irritable bowel syndrome, regional enteritis, spastic colon, postoperative ileus, ulcer, diarrhoea, the fever of stress-induced, the human immunodeficiency virus infection, neurodegenerative disease such as alzheimer's disease, Parkinson's disease and enjoy the court of a feudal ruler disease of pausing, gastrointestinal disease, eating disorder such as appetite stimulator and bulimia nervosa, the hemorrhagic stress reaction, chemical relies on or habituation, comprise for alcohol, Cocaine, heroine, benzodiazepine , or the dependence of other medicines or habituation, medicine or alcohol withdrawal symptom, the phrenoplegia of stress-induced, the normal sick syndrome of thyroid function, the syndrome of inappropriate antidiuresis hormone, obesity, Infertility, wound, spinal cord injuries receptor, the infringement of ischemic neurone, comprise cerebrum ischemia, cerebral hippocampus ischemic for example, the infringement of neurotoxin neurone, epilepsy, apoplexy, immune dysfunction comprises the immune dysfunction of stress-induced, comprise the pig tension syndrome, the ox ship fever, horse paroxysmal fibrillation, chicken imprison dysfunction, sheep sheering people animal nervous and dog interacts nervous, muscle spasm, the urinary incontinence, Alzheimer type senile dementia, multi-infarct dementia, amyotrophic lateral sclerosis, hypertension, tachycardia, congestive heart failure, osteoporosis, premature labor, hypoglycemia, with the syndrome X in Mammals or the bird, its comprise quantity be effective to treat the such obstacle or the state of an illness according to claim 1 compound and pharmaceutical carrier.
12. method that is used for following treatment: (a) obstacle or the state of an illness, its treatment can or promote by antagonism CRF influence, include but not limited to induce or promoted obstacle, (b) be selected from the following obstacle or the state of an illness: struvite obstacle such as rheumatic arthritis and osteoarthritis, pain, asthma, psoriasis and allergy by CRF; The universality anxiety disorder, frightened, phobia, comprise social phobia, agoraphobia and specific phobia disease, obsessional idea and behavior disease, stress disorder after the wound, by stress reaction inductive somnopathy, the pain sensation such as fibromyalgia, affective disorder such as melancholia, comprise major depression, single-shot is done depressed, the recurrent depression, child abuse inductive depression, the affective disorder relevant with syndrome before the menstruation, and postpartum depression, depression, bipolar disorder, cyclothymia, chronic tired syndrome, the headache of stress-induced, cancer, irritable bowel syndrome, regional enteritis, spastic colon, postoperative ileus, ulcer, diarrhoea, the fever of stress-induced, the human immunodeficiency virus infection, neurodegenerative disease such as alzheimer's disease, Parkinson's disease and enjoy the court of a feudal ruler disease of pausing, gastrointestinal disease, eating disorder such as appetite stimulator and bulimia nervosa, the hemorrhagic stress reaction, chemical relies on or habituation, comprise for alcohol, Cocaine, heroine, benzodiazepine , or the dependence of other medicines or habituation, medicine or alcohol withdrawal symptom, the phrenoplegia of stress-induced, the normal sick syndrome of thyroid function, the syndrome of inappropriate antidiuresis hormone, obesity, Infertility, wound, spinal cord injuries receptor, the infringement of ischemic neurone, comprise cerebrum ischemia, cerebral hippocampus ischemic for example, the infringement of neurotoxin neurone, epilepsy, apoplexy, immune dysfunction comprises the immune dysfunction of stress-induced, comprise the pig tension syndrome, the ox ship fever, horse paroxysmal fibrillation, chicken imprison dysfunction, sheep sheering people animal nervous and dog interacts nervous, muscle spasm, the urinary incontinence, Alzheimer type senile dementia, multi-infarct dementia, amyotrophic lateral sclerosis, hypertension, tachycardia, congestive heart failure, osteoporosis, premature labor, hypoglycemia, with the syndrome X in Mammals or the bird, comprise the obstacle that the object treatment that needs this treatment is such or the state of an illness significant quantity according to claim 1 compound.
13. a method for the treatment of the state of an illness comprises to treat the effective quantity of this state of an illness giving the compound of claim 1, wherein this state of an illness is selected from:
A) abnormal circadian rhythm;
B) depression wherein is used for the treatment of second kind of depressed compound in addition, and the described second kind of compound that is used for the treatment of depression is for described CRF antagonist, and its effect postpones; With
C) vomiting.
14. the method for claim 13, wherein the state of an illness is an abnormal circadian rhythm, and compound is combined with the second kind of compound that is used for the treatment of somnopathy.
15. the method for claim 14, wherein this second kind of compound is selected from tachykinin antagenists, is used for agonist, metalonergic compound, GABA brain receptor stimulant, the 5HT of GABA brain acceptor 2Receptor antagonist and D4 receptors bind thing.
16. the method for claim 13, wherein this state of an illness is depressed, and this second kind of compound that wherein has the depressed delayed action of treatment is selected from the selective serotonin reuptake inhibitor, tricyclic antidepressants, norepinephrine uptake inhibitors, lithium, Bupropion, Sertraline, fluoxetine, trazodone, with be selected from imipramine, amitriptyline, Trimipramine, doxepin, Desipramine, nortriptyline, protriptyline, amoxapine, clomipramine, maprotiline, with the tricyclic antidepressants of Carbamzepine and the pharmaceutical salts and the ester of above-claimed cpd.
17. the method for claim 13, wherein this state of an illness is vomiting, further comprises the second kind of compound that is used for the treatment of vomiting.
18. the method for claim 17, this second kind of compound that wherein is used for the treatment of vomiting is selected from tachykinin antagenists, 5HT3 antagonist, gaba agonist and Substance P inhibitor.
19. a pharmaceutical composition for the treatment of the state of an illness comprises the compound and the pharmaceutical carrier of the claim 1 of treatment this state of an illness effective quantity, wherein this state of an illness is selected from:
A) abnormal circadian rhythm;
B) depression wherein is used for the treatment of second kind of depressed compound in addition, and the described second kind of compound that is used for the treatment of depression is for described CRF antagonist, and its effect postpones; With
C) vomiting.
20. according to the pharmaceutical composition of claim 19, wherein the state of an illness is an abnormal circadian rhythm, and compound is combined with the second kind of compound that is used for the treatment of somnopathy.
21. according to the pharmaceutical composition of claim 20, wherein this second kind of compound is selected from tachykinin antagenists, is used for agonist, metalonergic compound, GABA brain receptor stimulant, the 5HT of GABA brain acceptor 2Receptor antagonist and D4 receptors bind thing.
22. pharmaceutical composition according to claim 19, wherein this state of an illness is depressed, and this second kind of compound that wherein has the depressed delayed action of treatment is selected from the selective serotonin reuptake inhibitor, tricyclic antidepressants, norepinephrine uptake inhibitors, lithium, Bupropion, Sertraline, fluoxetine, trazodone, with be selected from imipramine, amitriptyline, Trimipramine, doxepin, Desipramine, nortriptyline, protriptyline, amoxapine, clomipramine, maprotiline, with the tricyclic antidepressants of Carbamzepine and the pharmaceutical salts and the ester of above-claimed cpd.
23. according to the pharmaceutical composition of claim 19, wherein this state of an illness is vomiting, further comprises the second kind of compound that is used for the treatment of vomiting.
24. according to the pharmaceutical composition of claim 23, this second kind of compound that wherein is used for the treatment of vomiting is selected from tachykinin antagenists, 5HT3 antagonist, gaba agonist and Substance P inhibitor.
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